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Pharmacology & Therapeutics Jun 2021Many different forms of hormonal contraception are used by millions of women worldwide. These contraceptives differ in the dose and type of synthetic progestogenic... (Review)
Review
Many different forms of hormonal contraception are used by millions of women worldwide. These contraceptives differ in the dose and type of synthetic progestogenic compound (progestin) used, as well as the route of administration and whether or not they contain estrogenic compounds. There is an increasing awareness that different forms of contraception and different progestins have different side-effect profiles, in particular their cardiovascular effects, effects on reproductive cancers and susceptibility to infectious diseases. There is a need to develop new methods to suit different needs and with minimal risks, especially in under-resourced areas. This requires a better understanding of the pharmacokinetics, metabolism, serum and tissue concentrations of progestins used in contraception as well as the biological activities of progestins and their metabolites via steroid receptors. Here we review the current knowledge on these topics and identify the research gaps. We show that there is a paucity of research on most of these topics for most progestins. We find that major impediments to clear conclusions on these topics include a lack of standardized methodologies, comparisons between non-parallel clinical studies and variability of data on serum concentrations between and within studies. The latter is most likely due, at least in part, to differences in intrinsic characteristics of participants. The review highlights the importance of insight on these topics in order to provide the best contraceptive options to women with minimal risks.
Topics: Contraception; Contraceptive Agents; Female; Humans; Progestins
PubMed: 33316287
DOI: 10.1016/j.pharmthera.2020.107789 -
Molecular and Cellular Endocrinology Jun 2012Steroid hormones coordinate and control the development and function of many organs and are implicated in many pathological processes. Progesterone signaling, in... (Review)
Review
Steroid hormones coordinate and control the development and function of many organs and are implicated in many pathological processes. Progesterone signaling, in particular, is essential for several important female reproductive functions. Physiological effects of progesterone are mediated by its cognate receptor, expressed in a subset of cells in target tissues. Experimental evidence has accumulated that progesterone acts through both cell intrinsic as well as paracrine signaling mechanisms. By relegating the hormonal stimulus to paracrine signaling cascades the systemic signal gets amplified locally and signaling reaches different cell types that are devoid of hormone receptors. Interestingly, distinct biological responses to progesterone in different target tissues rely on several tissue-specific and some common paracrine factors that coordinate biological responses in different cell types. Evidence is forthcoming that the intercellular signaling pathways that control development and physiological functions are important in tumorigenesis.
Topics: Animals; Female; Humans; Paracrine Communication; Progesterone; Progestins; Signal Transduction
PubMed: 21945477
DOI: 10.1016/j.mce.2011.09.018 -
Drug Metabolism and Disposition: the... Jun 2023Combined oral contraceptives (COCs) are widely used in women of reproductive age in the United States. Metabolism plays an important role in the elimination of estrogens... (Review)
Review
Combined oral contraceptives (COCs) are widely used in women of reproductive age in the United States. Metabolism plays an important role in the elimination of estrogens and progestins contained in COCs. It is unavoidable that a woman using COCs may need to take another drug to treat a disease. If the concurrently used drug induces enzymes responsible for the metabolism of progestins and/or estrogens, unintended pregnancy or irregular bleeding may occur. If the concurrent drug inhibits the metabolism of these exogenous hormones, there may be an increased safety risk such as thrombosis. Therefore, for an investigational drug intended to be used in women with reproductive potential, evaluating its effects on the pharmacokinetics of COCs is important to determine if additional labeling is necessary for managing drug-drug interactions (DDIs) between the concomitant product and the COCs. It is challenging to determine when this clinical drug interaction study is needed, whether an observed exposure change of progestin/estrogen is clinically meaningful, and if the results of a clinical drug interaction study with one COC can predict exposure changes of unstudied COCs to inform labeling. In this review, we summarize the current understanding of metabolic pathways of estrogens and progestins contained in commonly used COCs and known interactions of these COCs as victim drugs and we discuss possible mechanisms of interactions for unexpected results. We also discuss recent advances, knowledge gaps, and future perspectives on this important topic. The review will enhance the understanding of DDIs with COCs and improve the safe and effective use of COCs. SIGNIFICANCE STATEMENT: This minireview provides an overview of the metabolic pathways of ethinyl estradiol and progestins contained in commonly used combined oral contraceptives (COCs) and significant drug interactions of these COCs as victims. It also discusses recent advances, knowledge gaps, future perspectives, and potential mechanisms for unexpected results of clinical drug interaction studies of COCs. This minireview will help the reader understand considerations when evaluating the drug interaction potential with COCs for drugs that are expected to be used concurrently.
Topics: Female; Humans; Contraceptives, Oral, Combined; Progestins; Ethinyl Estradiol; Estrogens; Drug Interactions
PubMed: 36963837
DOI: 10.1124/dmd.122.000854 -
Journal of Bacteriology Apr 2022Membrane potential homeostasis is essential for cell survival. Defects in membrane potential lead to pleiotropic phenotypes, consistent with the central role of membrane...
Membrane potential homeostasis is essential for cell survival. Defects in membrane potential lead to pleiotropic phenotypes, consistent with the central role of membrane energetics in cell physiology. Homologs of the progestin and AdipoQ receptors (PAQRs) are conserved in multiple phyla of and . In eukaryotes, PAQRs are proposed to modulate membrane fluidity and fatty acid (FA) metabolism. The role of bacterial homologs has not been elucidated. Here, we use Escherichia coli and Bacillus subtilis to show that bacterial PAQR homologs, which we name "TrhA," have a role in membrane energetics homeostasis. Using transcriptional fusions, we show that E. coli TrhA (encoded by ) is part of the unsaturated fatty acid biosynthesis regulon. Fatty acid analyses and physiological assays show that a lack of TrhA in both E. coli and B. subtilis (encoded by ) provokes subtle but consistent changes in membrane fatty acid profiles that do not translate to control of membrane fluidity. Instead, membrane proteomics in E. coli suggested a disrupted energy metabolism and dysregulated membrane energetics in the mutant, though it grew similarly to its parent. These changes translated into a disturbed membrane potential in the mutant relative to its parent under various growth conditions. Similar dysregulation of membrane energetics was observed in a different E. coli strain and in the distantly related B. subtilis. Together, our findings are consistent with a role for TrhA in membrane energetics homeostasis, through a mechanism that remains to be elucidated. Eukaryotic homologs of the progestin and AdipoQ receptor family (PAQR) have been shown to regulate membrane fluidity by affecting, through unknown mechanisms, unsaturated fatty acid (FA) metabolism. The bacterial homologs studied here mediate small and consistent changes in unsaturated FA metabolism that do not seem to impact membrane fluidity but, rather, alter membrane energetics homeostasis. Together, the findings here suggest that bacterial and eukaryotic PAQRs share functions in maintaining membrane homeostasis (fluidity in eukaryotes and energetics for bacteria with TrhA homologs).
Topics: Bacillus subtilis; Cell Membrane; Escherichia coli; Fatty Acids; Fatty Acids, Unsaturated; Homeostasis; Progestins
PubMed: 35285724
DOI: 10.1128/jb.00583-21 -
European Review For Medical and... Apr 2022Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of...
Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of hormones is pivotal to avoid dangerous states. Unopposed estrogens occur when progestogen levels do not balance estrogens, primarily deriving from overproduction of estrogens via aromatase enzyme. In the endometrium, unopposed estrogens induce proliferative or invasive phenomena, which represent the first step toward different diseases. These pathologies include endometrial hyperplasia, endometrial polyps, endometriosis and adenomyosis. Endometrial hyperplasia and polyps are proliferative pathologies, while endometriosis and adenomyosis are characterized by the invasion of other tissues by endometrial cells. Current pharmacological treatments include Gonadotropin-Releasing-Hormone analogs, aromatase inhibitors and progestogens, either alone or in combination with estrogens. As these drugs usually lead to burdensome undesired effects, researchers seek to find new therapeutical molecules. Recent literature highlights the positive effects of metformin, an insulin sensitizing drug that reduces the insulin proliferative stimulus on the endometrium. d-chiro-inositol is an insulin second messenger with insulin sensitizing and mimetic properties, recently described as an aromatase down-regulator. Based on current evidence, d-chiro-inositol may be useful to treat the pathologies responsive to unopposed estrogens.
Topics: Adenomyosis; Aromatase; Endometrial Hyperplasia; Endometriosis; Endometrium; Estrogens; Female; Humans; Inositol; Insulins; Progestins
PubMed: 35503642
DOI: 10.26355/eurrev_202204_28629 -
BMJ Sexual & Reproductive Health Apr 2021
Topics: Humans; Intrauterine Devices; Progestins; Reproductive Health Services
PubMed: 33850008
DOI: 10.1136/bmjsrh-2021-201095 -
Acta Obstetricia Et Gynecologica... Oct 2011Progestin supplementation appears to be a promising approach to both preventing initiation of preterm labor and treating it once it is already established, given the... (Review)
Review
Progestin supplementation appears to be a promising approach to both preventing initiation of preterm labor and treating it once it is already established, given the role of progesterone in maintaining pregnancy, as well as support from basic and clinical research. Progesterone and 17α-hydroxyprogesterone acetate slow the process of cervical ripening, and this is the rationale for prophylactic long-term progestin supplementation mostly studied so far. However, progesterone (but not 17α-hydroxyprogesterone acetate) also inhibits myometrial activity even after the cervix has already ripened. Moreover, these effects depend greatly on the vehicle used and the route of administration. Understanding different mechanisms of action, as well as the importance of progestin formulation, vehicle and route of administration, is the key to finding the optimal progestin treatment for prevention of preterm birth.
Topics: Administration, Intravaginal; Cervical Ripening; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Infant, Newborn; Injections, Intramuscular; Obstetric Labor, Premature; Pregnancy; Pregnancy Outcome; Premature Birth; Primary Prevention; Progestins; Randomized Controlled Trials as Topic
PubMed: 21564026
DOI: 10.1111/j.1600-0412.2011.01178.x -
Archives of Disease in Childhood Oct 2017Pubertal induction in girls with ovarian insufficiency aims to mimic normal puberty, a highly complex process. Here we amalgamate the sparse global evidence and propose... (Review)
Review
Pubertal induction in girls with ovarian insufficiency aims to mimic normal puberty, a highly complex process. Here we amalgamate the sparse global evidence and propose three options for pubertal induction regimens including oral ethinyloestradiol, and oral and transdermal 17β-oestradiol. The introduction of progestogens is discussed and the transition to hormone supplementation for adult women. The merits and disadvantages of the different options are detailed. The available evidence indicates that transdermal 17β-oestradiol has the most favourable efficacy, safety and cost profile but randomised controlled trials are urgently required to determine which regimen provides the best clinical outcomes.
Topics: Estradiol; Female; Hormone Replacement Therapy; Humans; Primary Ovarian Insufficiency; Progestins; Puberty
PubMed: 28446424
DOI: 10.1136/archdischild-2016-311372 -
Frontiers in Endocrinology 2022The purpose of this study is to assess the safety of progestin-primed ovarian stimulation (PPOS) protocol regarding the neonatal outcomes and congenital malformations in...
PURPOSE
The purpose of this study is to assess the safety of progestin-primed ovarian stimulation (PPOS) protocol regarding the neonatal outcomes and congenital malformations in babies born after fertilization (IVF) and frozen embryo transfer (FET).
METHODS
In this large retrospective cohort study, a total of 16,493 infants born between 1 September 2013 and 31 July 2021 from IVF and FET cycles after treatment with either PPOS (n = 15,245) or gonadotropin-releasing hormone antagonist (GnRH-ant) (n = 1,248) were finally enrolled. The primary outcome measure was the incidence of congenital malformations. The secondary outcome measures were rates of low birth weight (LBW), very low birth weight (VLBW), preterm birth (PTB), very preterm birth (VPTB), and early neonatal death.
RESULTS
Birth characteristics for both singletons and twins regarding the sex of infants, gestational age, birth weight, and birth length were comparable between the PPOS group and the GnRH-ant group. Rates of LBW, VLBW, PTB, VPTB, and early neonatal death were also similar. The reanalysis using propensity score matching (PSM) and multivariable logistic regression indicated that the PPOS protocol could not increase the risk of adverse neonatal outcomes compared with the GnRH-ant protocol. Furthermore, no significant difference was observed in the overall incidence of congenital malformations in live-born babies. After PSM and controlling for all confounders, the results remained insignificant with an adjusted odds ratio of 0.66 [95% confidence interval (CI) 0.32-1.34] and 2.43 [95% CI 0.97-6.06], respectively, for singletons and twins.
CONCLUSIONS
Our study suggests that compared with GnRH-ant treatment for IVF, the PPOS protocol could not produce a negative effect on the newborn population in terms of neonatal outcomes and congenital malformations.
Topics: Infant; Child; Female; Infant, Newborn; Humans; Progestins; Premature Birth; Retrospective Studies; Perinatal Death; Ovulation Induction; Hormone Antagonists; Gonadotropin-Releasing Hormone
PubMed: 36440198
DOI: 10.3389/fendo.2022.965863 -
Women's Health (London, England) Mar 2008Progesterone is an ovarian steroid hormone that is essential for normal breast development during puberty and in preparation for lactation and breastfeeding. The actions... (Review)
Review
Progesterone is an ovarian steroid hormone that is essential for normal breast development during puberty and in preparation for lactation and breastfeeding. The actions of progesterone are primarily mediated by its high-affinity receptors, which include the classical progesterone receptor (PR)-A and -B isoforms, located in diverse tissues, including the brain, where progesterone controls reproductive behavior, and the breast and reproductive organs. Progestins are frequently prescribed for contraception or during postmenopausal hormone replacement therapy, in which progestins are combined with estrogen as a means to block estrogen-induced endometrial growth. The role of estrogen as a potent breast mitogen is undisputed, and inhibitors of the estrogen receptor and estrogen-producing enzymes (aromatases) are effective first-line cancer therapies. However, PR action in breast cancer is grossly understudied and remains controversial. Herein, we review existing evidence and discuss the challenges to defining a role for progesterone in breast cancer.
Topics: Animals; Breast; Breast Neoplasms; Estrogen Replacement Therapy; Female; Haplorhini; Humans; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Mice; Progesterone; Progestins; Rats; Receptors, Progesterone
PubMed: 19072517
DOI: 10.2217/17455057.4.2.151