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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 -
BMJ Sexual & Reproductive Health Apr 2021
Topics: Humans; Intrauterine Devices; Progestins; Reproductive Health Services
PubMed: 33850008
DOI: 10.1136/bmjsrh-2021-201095 -
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 -
International Journal of Molecular... Oct 2021To evaluate the effectiveness of a new class of medical drugs, namely oral gonadotropin-releasing hormone (GnRH) antagonists, in the management of premenopausal women... (Review)
Review
To evaluate the effectiveness of a new class of medical drugs, namely oral gonadotropin-releasing hormone (GnRH) antagonists, in the management of premenopausal women with endometriosis-associated pelvic pain. We reviewed the most relevant papers ( = 27) on the efficacy of new medical alternatives (oral GnRH antagonists) as therapy for endometriosis. We first briefly summarized the concept of progesterone resistance and established that oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis. Since clinical evidence shows that estrogens play a critical role in the pathogenesis of the disease, lowering their levels with oral GnRH antagonists may well prove effective, especially in women who fail to respond to progestogens. There is a need for reliable long-term oral treatment capable of managing endometriosis symptoms, taking into consideration both the main symptoms and phenotype of the disease. Published studies reviewed and discussed here confirm the efficacy of GnRH antagonists. There is a place for GnRH antagonists in the management of symptomatic endometriosis. Novel algorithms that take into account the different phenotypes are proposed.
Topics: Endometriosis; Estradiol; Female; Gonadotropin-Releasing Hormone; Hormone Antagonists; Hormone Replacement Therapy; Humans; Infertility; Pain; Progestins
PubMed: 34768770
DOI: 10.3390/ijms222111342 -
Fertility and Sterility Sep 2014Although fibroids are common benign tumors, their impact on women's quality of life can be considerable. The most frequent symptoms are uterine bleeding, resulting in... (Review)
Review
Although fibroids are common benign tumors, their impact on women's quality of life can be considerable. The most frequent symptoms are uterine bleeding, resulting in anemia, and pelvic pain. Fibroids can be of genetic or hormonal origin or arise from intrauterine events. Current options for medical treatment include control of estradiol and progesterone production or action and are discussed in this review. Although curative treatment of fibroids relies on surgical strategies, the current trend is for uterine-sparing treatment to preserve fertility and avoid unnecessary surgery. Currently approved medical treatments include intrauterine progestin delivery to reduce uterine bleeding, GnRH analogues, and, more recently, selective progesterone receptor modulators to control uterine bleeding and reduce fibroid volume.
Topics: Antineoplastic Agents, Hormonal; Cell Proliferation; Female; Humans; Leiomyoma; Progestins; Selective Estrogen Receptor Modulators; Tumor Burden; Uterine Neoplasms
PubMed: 25171950
DOI: 10.1016/j.fertnstert.2014.07.1238 -
Cancer Medicine Mar 2023Progestins are used as fertility-sparing regimens for young patients with stage 1A endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH)....
BACKGROUND
Progestins are used as fertility-sparing regimens for young patients with stage 1A endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH). CD163 macrophages promote estrogen-dependent EEC development, but whether they induce progestin insensitivity remains unclear. This study aimed to investigate the possible effects of CD163 macrophages on progestin response in AEH/EEC patients.
METHODS
The number of infiltrating CD163 macrophages in progestin-insensitive and -sensitive endometrial lesions was compared. The effects of CD163 macrophages on progestin responses and progesterone receptor (PR) expression in EC cells were evaluated in vitro. ATAC-seq and RNA-seq were combined to identify molecular/biological changes induced by CD163 macrophages in progestin-insensitive EC cells.
RESULTS
Increased CD163 macrophage infiltration was significantly associated with progestin insensitivity and longer treatment durations in AEH/EEC patients. Additionally, the number of CD163 macrophages was negatively correlated with PR expression in AEH/EEC tissues. Furthermore, the CD163 macrophage-mediated microenvironment and secreted cytokines downregulated PR expression and impaired the response of EC cells to medroxyprogesterone acetate (MPA). RNA-seq analysis demonstrated that CD163 macrophages antagonized PR signaling by blocking or even reversing MPA-regulated differential gene expression. Based on RNA-seq and ATAC-seq analyses, extracellular matrix (ECM) signaling and ECM-related transcription factors, FOXF2, POU1F1, and RUNX1were identified to potentially be involved in CD163 macrophage-induced progestin insensitivity in endometrial cancer patients.
CONCLUSIONS
We identified CD163 macrophages as an important mediator of progestin desensitization and an unfavorable factor for the efficacy of fertility-preserving treatment in AEH/EEC patients.
Topics: Female; Humans; Progestins; Chromatin Immunoprecipitation Sequencing; RNA-Seq; Endometrial Neoplasms; Medroxyprogesterone Acetate; Progesterone; Endometrial Hyperplasia; Carcinoma, Endometrioid; Macrophages; Tumor Microenvironment; Forkhead Transcription Factors
PubMed: 36373483
DOI: 10.1002/cam4.5396 -
Vascular Pharmacology Oct 2023Vascular endothelial and smooth muscle cell dysfunction proceed the development of numerous vascular diseases, such as atherosclerosis. Both estrogen and progesterone... (Review)
Review
Vascular endothelial and smooth muscle cell dysfunction proceed the development of numerous vascular diseases, such as atherosclerosis. Both estrogen and progesterone receptors are present on vascular endothelial and smooth muscle cells, and therefore it has been postulated that these compounds may affect vascular function. It has been well-established that estrogen is a vasoprotective compound, however, the effects of progesterone on vascular function are not well understood. This narrative review summarizes the current research investigating the impact of both endogenous progesterone, and exogenous synthetic progestin on vascular endothelial and smooth muscle cell function and identifies discrepancies on their effects in vitro and in vivo. We speculate that an inverted-U dose response curve may exist between nitric oxide bioavailability and progesterone concentration, and that the androgenic properties of a progestin may influence vascular function. Future research is needed to discern the effects of both endogenous progesterone and exogenous progestin on vascular endothelial and smooth muscle cell function with consideration for the impacts of progesterone/progestin dose, and progestin type.
Topics: Humans; Progestins; Progesterone; Progesterone Congeners; Estrogens; Endothelial Cells; Atherosclerosis; Myocytes, Smooth Muscle
PubMed: 37591444
DOI: 10.1016/j.vph.2023.107209 -
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 -
Medecine Sciences : M/S Oct 2021Obese women are at high risk of unintended pregnancy. In addition, obesity is an important risk factor for venous thromboembolism events and arterial thrombosis. All of...
Obese women are at high risk of unintended pregnancy. In addition, obesity is an important risk factor for venous thromboembolism events and arterial thrombosis. All of these data are to be considered in choosing a contraceptive method for obese women. The metabolic changes and the increased body mass of these women may be the cause of a reduction in the effectiveness of hormonal contraception. The progestin-only contraceptives (progestin only pills and etonogestrel subdermal implant) and the intra-uterine devices are the preferred contraceptive methods in women with obesity. The combined estrogen-progestin contraceptives may be proposed in young obese women without other cardiovascular risk factor. Obesity per se does not seem to increase the risk of failure of most contraceptive methods. Bariatric surgery is a complex situation. Contraception is needed for at least 12 months after surgery. Some bariatric surgery such as bypass can induce gastrointestinal malabsorption. In this situation, all oral contraceptives are not recommended because of a higher risk of failure.
Topics: Contraception; Contraceptives, Oral, Hormonal; Female; Humans; Obesity; Pregnancy; Progestins; Risk Factors
PubMed: 34647876
DOI: 10.1051/medsci/2021147 -
European Journal of Sport Science Jul 2022Sex steroids, commonly referred to as sex hormones, are integral to the development and maintenance of the human reproductive system. In addition, male (androgens) and... (Review)
Review
Sex steroids, commonly referred to as sex hormones, are integral to the development and maintenance of the human reproductive system. In addition, male (androgens) and female (estrogens and progestogens) sex hormones promote the development of secondary sex characteristics by targeting a range of other tissues, including skeletal muscle. The role of androgens on skeletal muscle mass, function and metabolism has been well described in males, yet female specific studies are scarce in the literature. This narrative review summarises the available evidence around the mechanistic role of androgens, estrogens and progestogens in female skeletal muscle. An analysis of the literature indicates that sex steroids play important roles in the regulation of female skeletal muscle mass and function. The free fractions of testosterone and progesterone in serum were consistently associated with the regulation of muscle mass, while estrogens may be primarily involved in mediating the muscle contractile function in conjunction with other sex hormones. Muscle strength was however not directly associated with any hormone in isolation when at physiological concentrations. Importantly, recent evidence suggests that intramuscular sex hormone concentrations may be more strongly associated with muscle size and function than circulating forms, providing interesting opportunities for future research. By combining cross-sectional, interventional and mechanical studies, this review aims to provide a broad, multidisciplinary picture of the current knowledge of the effects of sex steroids on skeletal muscle in females, with a focus on the regulation of muscle size and function and an insight into their clinical implications. HighlightsFree testosterone, but not total testosterone, is associated with lean mass but not strength in pre- and post-menopausal females.Progesterone and estrogens may regulate muscle mass and strength, respectively, in females.Intra-muscular steroids may be more closely associated to muscle mass and strength, compared to systemic fractions.
Topics: Androgens; Cross-Sectional Studies; Estrogens; Female; Gonadal Steroid Hormones; Humans; Male; Muscle, Skeletal; Progesterone; Progestins; Steroids; Testosterone
PubMed: 33890831
DOI: 10.1080/17461391.2021.1921854