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International Journal of Molecular... Dec 2022Recurrent pregnancy losses (RPL) is a common reproductive disorder with various underlying etiologies. In recent years, rapid progress has been made in exploring the... (Review)
Review
Recurrent pregnancy losses (RPL) is a common reproductive disorder with various underlying etiologies. In recent years, rapid progress has been made in exploring the immunological mechanisms for RPL. A propensity toward Th2 over Th1 and regulatory T (Treg) over Th17 immune responses may be advantageous for reproductive success. In women with RPL and animals prone to abortion, an inordinate expression of cytokines associated with implantation and early embryo development is present in the endometrium or decidua secreted from immune and non-immune cells. Hence, an adverse cytokine milieu at the maternal-fetal interface assaults immunological tolerance, leading to fetal rejection. Similar to T cells, NK cells can be categorized based on the characteristics of cytokines they secrete. Decidual NK (dNK) cells of RPL patients exhibited an increased NK1/NK2 ratio (IFN-γ/IL-4 producing NK cell ratios), leading to pro-inflammatory cytokine milieu and increased NK cell cytotoxicity. Genetic polymorphism may be the underlying etiologies for Th1 and Th17 propensity since it alters cytokine production. In addition, various hormones participate in cytokine regulations, including progesterone and estrogen, controlling cytokine balance in favor of the Th2 type. Consequently, the intricate regulation of cytokines and hormones may prevent the RPL of immune etiologies. Local or systemic administration of cytokines or their antagonists might help maintain adequate cytokine milieu, favoring Th2 over Th1 response or Treg over Th17 immune response in women with RPL. Herein, we provided an updated comprehensive review regarding the immune-regulatory role of pro- and anti-inflammatory cytokines in RPL. Understanding the roles of cytokines involved in RPL might significantly advance the early diagnosis, monitoring, and treatment of RPL.
Topics: Pregnancy; Humans; Animals; Female; Cytokines; Abortion, Habitual; Killer Cells, Natural; Progesterone; Anti-Inflammatory Agents
PubMed: 36613575
DOI: 10.3390/ijms24010132 -
Lancet (London, England) Mar 2020The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2... (Review)
Review
The development and approval of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer represents a major milestone in cancer therapeutics. Three different oral CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, have significantly improved progression-free survival by a number of months when combined with endocrine therapy. More recently, improvement in overall survival has been reported with ribociclib and abemaciclib. The toxicity profile of all three drugs is well described and generally easily manageable with dose reductions when indicated. More myelotoxicity is observed with palbociclib and ribociclib, but more gastrointestinal toxicity is observed with abemaciclib. Emerging data is shedding light on the resistance mechanisms associated with CDK4/6 inhibitors, including cell cycle alterations and activation of upstream tyrosine kinase receptors. A number of clinical trials are exploring several important questions regarding treatment sequencing, combinatorial strategies, and the use of CDK4/6 inhibitors in the adjuvant and neoadjuvant settings, thereby further expanding and refining the clinical application of CDK4/6 inhibitors for patients with breast cancer.
Topics: Breast Neoplasms; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Forecasting; Humans; Protein Kinase Inhibitors; Receptors, Estrogen; Receptors, Progesterone
PubMed: 32145796
DOI: 10.1016/S0140-6736(20)30165-3 -
Future Oncology (London, England) Mar 2022Hormone receptor (HR)-positive, HER2-negative tumors represent the most common form of metastatic breast cancer (MBC), and endocrine therapy has been the mainstay... (Review)
Review
Hormone receptor (HR)-positive, HER2-negative tumors represent the most common form of metastatic breast cancer (MBC), and endocrine therapy has been the mainstay treatment for several decades. Recently, a novel drug class called CDK4/6 inhibitors in combination with endocrine therapy have remarkably improved the outcome of patients with HR-positive, HER2-negative MBC by targeting the cell cycle machinery and overcoming aspects of endocrine resistance. Several potential cell-cycle-specific and nonspecific mechanisms of resistance to CDK4/6 inhibitors have been reported in recent studies. This review discusses potential resistance mechanisms to CDK4/6 inhibitors, the use of biomarkers to guide treatment for HR-positive, HER2-negative MBC and possible approaches to overcome resistance to CDK4/6 inhibitors.
Topics: Biomarkers, Tumor; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Protein Kinase Inhibitors; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone
PubMed: 35137602
DOI: 10.2217/fon-2021-0842 -
The Journal of Clinical Endocrinology... Feb 2022Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production....
CONTEXT
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production.
OBJECTIVE
This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD.
METHODS
This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.
RESULTS
Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios.
CONCLUSION
Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; 17-alpha-Hydroxyprogesterone; Administration, Oral; Adrenal Hyperplasia, Congenital; Adrenocorticotropic Hormone; Androstenedione; Azabicyclo Compounds; Biomarkers; Dose-Response Relationship, Drug; Oxadiazoles; Receptors, Corticotropin-Releasing Hormone; Testosterone; Treatment Outcome
PubMed: 34653252
DOI: 10.1210/clinem/dgab749 -
Future Oncology (London, England) Jun 2021This review aims to qualitatively summarize the published real-world evidence (RWE) for CDK4/6 inhibitors (CDK4/6i) approved for treating HR+, HER2-negative...
This review aims to qualitatively summarize the published real-world evidence (RWE) for CDK4/6 inhibitors (CDK4/6i) approved for treating HR+, HER2-negative advanced/metastatic breast cancer (HR+/HER2- a/mBC). A systematic literature review was conducted to identify RWE studies of CDK4/6i in HR+/HER2- a/mBC published from 2015 to 2019. This review identified 114 studies, of which 85 were only presented at scientific conferences. Most RWE studies investigated palbociclib and demonstrated improved outcomes. There are limited long-term and comparative data between CDK4/6i and endocrine monotherapy, and within the CDK4/6i class. Available RWE suggests that CDK4/6i are associated with improved outcomes in HR+/HER2- a/mBC, although additional studies with longer follow-up periods are needed.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Estrogen Receptor alpha; Female; Humans; Neoplasm Metastasis; Neoplasm Staging; Receptor, ErbB-2; Receptors, Progesterone; Treatment Outcome
PubMed: 33663223
DOI: 10.2217/fon-2020-1264 -
The New England Journal of Medicine Jul 2019An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival.
METHODS
We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
RESULTS
A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval [CI], 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87).
CONCLUSIONS
This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).
Topics: Adult; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Cyclin-Dependent Kinases; Double-Blind Method; Female; Follow-Up Studies; Humans; Intention to Treat Analysis; Middle Aged; Perimenopause; Premenopause; Protein Kinase Inhibitors; Purines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Survival Analysis; Tamoxifen
PubMed: 31166679
DOI: 10.1056/NEJMoa1903765 -
The Journal of Clinical Endocrinology... Oct 2023Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital...
CONTEXT
Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin.
OBJECTIVE
To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH.
METHODS
This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone.
RESULTS
8 participants (3 males, 5 females) were enrolled; median age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone.
CONCLUSION
Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.
Topics: Male; Adult; Humans; Female; Adolescent; Androgens; Adrenal Hyperplasia, Congenital; Androstenedione; 17-alpha-Hydroxyprogesterone; Testosterone; Adrenocorticotropic Hormone
PubMed: 37216921
DOI: 10.1210/clinem/dgad270 -
Hormone Molecular Biology and Clinical... May 2020Progestational agents are often prescribed to increase the clinical pregnancy rate in assisted reproduction. Progestogens affect implantation, cytokine balance, natural... (Review)
Review
Progestational agents are often prescribed to increase the clinical pregnancy rate in assisted reproduction. Progestogens affect implantation, cytokine balance, natural killer cell activity, arachidonic acid release and myometrial contractility. Progesterone production from the corpus luteum is essential for reproduction, but assisted reproductive technologies (ART) can impair luteal function. ART cycles can be classified into three, fresh cycles in which there may or may not be luteal insufficiency, agonist or antagonist cycles in which there is luteal insufficiency, and luteal support is essential, and donor cycles, in which there is no corpus luteum, and a luteal phase has to be created. However, there is no adequate diagnostic test for luteal insufficiency. This article summarises the effect of various progestogens, progesterone itself whether administered vaginally, intra-muscularly, rectally or subcutaneously, and the effect of the progestogen, dydrogesterone. The time of commencement and cessation of therapy are also discussed. Progestogens are also often used to treat threatened and recurrent miscarriage. In these patients progestogen supplementation may need to be prolonged. In threatened miscarriage, until after all bleeding stops, and in recurrent miscarriage, at least as long as the luteo-placental shift.
Topics: Clinical Decision-Making; Clinical Trials as Topic; Disease Management; Endometrium; Female; Fertilization in Vitro; Humans; Luteal Phase; Pregnancy; Progesterone; Progestins; Reproductive Techniques, Assisted; Treatment Outcome
PubMed: 32432564
DOI: 10.1515/hmbci-2019-0067 -
Frontiers in Endocrinology 2021A Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment.
BACKGROUND
A Delphi consensus was conducted to evaluate global expert opinions on key aspects of assisted reproductive technology (ART) treatment.
METHODS
Ten experts plus the Scientific Coordinator discussed and amended statements plus supporting references proposed by the Scientific Coordinator. The statements were distributed an online survey to 35 experts, who voted on their level of agreement or disagreement with each statement. Consensus was reached if the proportion of participants agreeing or disagreeing with a statement was >66%.
RESULTS
Eighteen statements were developed. All statements reached consensus and the most relevant are summarised here. (n = 9 statements): Recombinant human follicle stimulating hormone (r-hFSH) alone is sufficient for follicular development in normogonadotropic patients aged <35 years. Oocyte number and live birth rate are strongly correlated; there is a positive linear correlation with cumulative live birth rate. Different r-hFSH preparations have identical polypeptide chains but different glycosylation patterns, affecting the biospecific activity of r-hFSH. r-hFSH plus recombinant human LH (r-hFSH:r-hLH) demonstrates improved pregnancy rates and cost efficacy versus human menopausal gonadotropin (hMG) in patients with severe FSH and LH deficiency. (n = 2 statements): Gonadotropin releasing hormone (GnRH) antagonists are associated with lower rates of any grade ovarian hyperstimulation syndrome (OHSS) and cycle cancellation versus GnRH agonists. (n=4 statements): Human chorionic gonadotropin (hCG) represents the gold standard in fresh cycles. The efficacy of hCG triggering for frozen transfers in modified natural cycles is controversial compared with LH peak monitoring. Current evidence supports significantly higher pregnancy rates with hCG + GnRH agonist versus hCG alone, but further evidence is needed. GnRH agonist trigger, in GnRH antagonist protocol, is recommended for final oocyte maturation in women at risk of OHSS. (n = 3 statements): Vaginal progesterone therapy represents the gold standard for luteal-phase support.
CONCLUSIONS
This Delphi consensus provides a real-world clinical perspective on the specific approaches during the key steps of ART treatment from a diverse group of international experts. Additional guidance from clinicians on ART strategies could complement guidelines and policies, and may help to further improve treatment outcomes.
Topics: Chorionic Gonadotropin; Consensus; Delphi Technique; Female; Fertilization in Vitro; Follicle Stimulating Hormone, Human; Gonadotropin-Releasing Hormone; Humans; Luteal Phase; Oocytes; Oogenesis; Ovulation Induction; Pituitary Gland; Practice Guidelines as Topic; Pregnancy; Progesterone; Reproductive Techniques, Assisted
PubMed: 34040586
DOI: 10.3389/fendo.2021.675670 -
Neuroscience Letters Jan 2021Progesterone acts on neurons directly by activating its receptor and through metabolic conversion to neurosteroids. There is emerging evidence that progesterone exerts... (Review)
Review
Progesterone acts on neurons directly by activating its receptor and through metabolic conversion to neurosteroids. There is emerging evidence that progesterone exerts excitatory effects by activating its cognate receptors (progesterone receptors, PRs) through enhanced expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Progesterone metabolite 5α,3α-tetrahydro-progesterone (allopregnanolone, THP) mediates its anxiolytic and sedative actions through the potentiation of synaptic and extrasynaptic γ-aminobutyric acid type-A receptors (GABARs). Here, we review progesterone's neuromodulatory actions exerted through PRs and THP and their opposing role in regulating seizures, catamenial epilepsy, and seizure exacerbation associated with progesterone withdrawal.
Topics: Animals; Anticonvulsants; Epilepsy; GABA-A Receptor Antagonists; Humans; Neurons; Progesterone; Receptors, GABA-A; Receptors, Progesterone
PubMed: 33421486
DOI: 10.1016/j.neulet.2020.135619