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1.
J Environ Sci (China) ; 127: 375-388, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36522069

RESUMO

Altrenogest (ALT), drospirenone (DRO), and melengestrol acetate (MLA) are three highly potent synthetic progestins that can be released into agricultural soils, while their fate in soil minerals remains unclear. This study explored the transformation of these progestins in MnO2, SiO2, and ferrihydrite suspensions and identified their transformation products (TPs) via high resolution mass spectrometry and density functional theory calculations. Transformations were only observed for DRO and MLA in SiO2 suspension and ALT in MnO2 suspension (half-lives = 0.86 min - 9.90 day). ALT transformation was facilitated at higher MnO2 loadings, while DRO and MLA transformations were inhibited at higher SiO2 loadings. These data indicated that hydrophobic partitioning interaction was dominant at higher SiO2 loadings rather than specific interaction, which limited subsequent surface-catalyzed transformation. ALT transformation rate decreased with increasing pH because MnO2 reduction requires proton participation. In contrast, relatively high pH facilitated MLA and DRO transformation, indicating that base-catalyzed hydrolysis occurred in SiO2 suspension. The clustermap demonstrated the formation of abundant TPs. Lactone ring and acetoxy group hydrolysis was the major transformation pathway for DRO and MLA, with estimated yields of 57.7% and 173.2% at 6 day, respectively. ALT experienced C12 hydroxylation and formed the major TP 326g (yield of 15.4% at 8 hr). ALT also experienced allyl group oxidation and subsequent C5 hydroxylation, forming the major TP 344a (yield of 14.1% at 8 hr). This study demonstrates that TPs of metastable progestins are likely the main species in soils and that TP identification is a particular priority for risk assessment.


Assuntos
Compostos de Manganês , Solo , Solo/química , Progestinas , Suspensões , Dióxido de Silício , Óxidos , Minerais , Congêneres da Progesterona , Oxirredução
2.
J Hazard Mater ; 446: 130684, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36586332

RESUMO

Gestodene (GES), altrenogest (ALT), and medroxyprogesterone acetate (MPA) are three potent synthetic progestins detected in agricultural soils; however, their biotransformation outcomes in soils remain unclear. This study explored the biotransformation of these progestins in five agricultural soils with different physicochemical properties. The biotransformation data were well-described by a first-order decay model (R2 = 0.83-0.99), with estimated half-lives ranging between 12.1 and 188 h. Amplicon sequencing indicated that the presence of progestins changed the bacterial richness and community structure in the soils. Linear correlation, canonical correlation, and two-way correlation network analysis revealed that soil properties can affect biotransformation rates by interfering with progestin-soil interactions or with keystone taxa in soils. The clustermap demonstrated the formation of abundant transformation products (TPs). Isomerization and C4(5) hydrogenation were the major transformation pathways for GES (yields of ∼ 13.7 % and ∼ 10.6 %, respectively). Aromatic dehydrogenation was the major transformation pathway for ALT (yield of ∼ 17.4 %). The C17 hydrolysis with subsequent dehydration and hydrogenation was the major transformation pathway for MPA (yield of ∼ 196 %). In particular, some TPs exhibited progestagenic, androgenic, or estrogenic activity. This study highlights the importance of evaluating the ecotoxicity of progestin and TP mixtures for better understanding their risks in the environment.


Assuntos
Progestinas , Solo , Cinética , Solo/química , Biotransformação , Congêneres da Progesterona , Esteroides
3.
Front Endocrinol (Lausanne) ; 13: 959396, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36187129

RESUMO

Progestins, synthetic compounds designed to mimic the activity of natural progesterone (P4), are used globally in menopausal hormone therapy. Although the older progestins medroxyprogesterone acetate (MPA) and norethisterone (NET) have been implicated in increased breast cancer risk, little is known regarding newer progestins, and no significant risk has been associated with P4. Considering that breast cancer is the leading cause of mortality in women, establishing which progestins increase breast cancer incidence and elucidating the underlying mechanisms is a global priority. We showed for the first time that the newer-generation progestin drospirenone (DRSP) is the least potent progestin in terms of proliferation of the estrogen-responsive MCF-7 BUS breast cancer cell line, while NET and P4 have similar potencies to estradiol (E2), the known driver of breast cancer cell proliferation. Notably, MPA, the progestin most frequently associated with increased breast cancer risk, was significantly more potent than E2. While all the progestogens enhanced the anchorage-independent growth of the MCF-7 BUS cell line, MPA promoted a greater number of colonies than P4, NET or DRSP. None of the progestogens inhibited E2-induced proliferation and anchorage-independent growth. We also showed that under non-estrogenic conditions, MPA and NET, unlike P4 and DRSP, increased the expression of the estrogen receptor (ER) target gene, cathepsin D, via a mechanism requiring the co-recruitment of ERα and the progesterone receptor (PR) to the promoter region. In contrast, all progestogens promoted the association of the PR and ERα on the promoter of the PR target gene, MYC, thereby increasing its expression under non-estrogenic and estrogenic conditions. These results suggest that progestins differentially regulate the way the PR and ER converge to modulate the expression of PR and ER-regulated genes. Our novel findings indicating similarities and differences between P4 and the progestins, emphasize the importance of comparatively investigating effects of individual progestins rather than grouping them as a class. Further studies are required to underpin the clinical relevance of PR/ERα crosstalk in response to different progestins in both normal and malignant breast tissue, to either confirm or refute their suitability in combination therapy for ER-positive breast cancer.


Assuntos
Neoplasias da Mama , Receptores de Progesterona , Neoplasias da Mama/patologia , Catepsina D/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Acetato de Medroxiprogesterona/efeitos adversos , Noretindrona/efeitos adversos , Progesterona/farmacologia , Congêneres da Progesterona/efeitos adversos , Progestinas/farmacologia , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Regulação para Cima
4.
Front Endocrinol (Lausanne) ; 13: 888510, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36147581

RESUMO

The central nervous system effects of oral contraceptives (OCs) are not well-documented. In a set of 3 studies, we investigated a specific cognitive function, mental rotation, in healthy women currently using OCs for contraceptive purposes (n = 201) and in medication-free controls not using OCs (n = 44). Mental rotation was measured using a well-standardized and extensively validated psychometric test, the Vandenberg Mental Rotations Test (MRT). In an initial study (Study 1), current OC users (n = 63) were tested during the active or inactive phases of the contraceptive cycle in a parallel-groups design. Studies 2 and 3 were based on an archival dataset (n = 201 current OC users) that consisted of data on the MRT collected in real-time over a 30-year period and compiled for purposes of the present work. The OCs were combined formulations containing ethinyl estradiol (10-35 ug/day) plus a synthetic progestin. All 4 families of synthetic progestins historically used in OCs were represented in the dataset. Cognitive performance was evaluated during either active OC use ('active phase') or during the washout week of the contraceptive cycle ('inactive phase') when OC steroids are not used. The results showed a significant phase-of-cycle (POC) effect. Accuracy on the MRT was mildly diminished during the active phase of OC use, while scores on verbal fluency and speeded motor tasks were modestly improved. The POC effect was most evident in women using OCs that contained first- or second-generation progestins (the estrane family of progestins or OCs containing levonorgestrel), but not in women using OCs containing recently developed progestins and lower doses of ethinyl estradiol. Using independently established ratings of the estrogenic, androgenic, and progestogenic intensities of the different OC formulations, each brand of OC was classified according to its distinct endocrine profile. Multiple regression revealed that the effects of OC use on the MRT could be predicted based on the estrogenic strength of the contraceptives used. Estrogenic potency, not androgenic or anti-androgenic effects of the OC pill, may underlie the effects of OC usage on spatial cognition.


Assuntos
Levanogestrel , Progestinas , Cognição , Anticoncepcionais Orais/farmacologia , Estranos , Etinilestradiol/farmacologia , Feminino , Humanos , Congêneres da Progesterona , Progestinas/farmacologia
5.
Sci Rep ; 12(1): 11791, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35821038

RESUMO

Progesterone receptor (PR) transcriptional activity is a key factor in the differentiation of the uterine endometrium. By consequence, progestin has been identified as an important treatment modality for endometrial cancer. PR transcriptional activity is controlled by extracellular-signal-regulated kinase (ERK) mediated phosphorylation, downstream of growth factor receptors such as EGFR. However, phosphorylation of PR also targets it for ubiquitination and destruction in the proteasome. Quantitative studies of these opposing roles are much needed toward validation of potential new progestin-based therapeutics. In this work, we propose a spatial stochastic model to study the effects of the opposing roles for PR phosphorylation on the levels of active transcription factor. Our numerical simulations confirm earlier in vitro experiments in endometrial cancer cell lines, identifying clustering as a mechanism that amplifies the ability of progesterone receptors to influence gene transcription. We additionally show the usefulness of a statistical method we developed to quantify and control variations in stochastic simulations in general biochemical systems, assisting modelers in defining minimal but meaningful numbers of simulations while guaranteeing outputs remain within a pre-defined confidence level.


Assuntos
Neoplasias do Endométrio , Receptores de Progesterona , Análise por Conglomerados , Neoplasias do Endométrio/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Progesterona/farmacologia , Congêneres da Progesterona , Progestinas/farmacologia , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Transdução de Sinais , Translocação Genética
6.
Acta Obstet Gynecol Scand ; 101(8): 846-855, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35633036

RESUMO

INTRODUCTION: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. MATERIAL AND METHODS: All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. RESULTS: Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). CONCLUSIONS: An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.


Assuntos
Tromboembolia Venosa , Acetatos , Idoso , Anticoncepção , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Hormonais/efeitos adversos , Ciproterona , Estradiol , Estrogênios/efeitos adversos , Feminino , Humanos , Congêneres da Progesterona , Progestinas/efeitos adversos , Estudos Prospectivos , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/epidemiologia
7.
Gen Comp Endocrinol ; 321-322: 114025, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35292264

RESUMO

Nuclear progestin receptor (PGR), which is induced in the follicles destined to undergo ovulation, is believed to be obligatory for rupture of the follicles during ovulation in vertebrates. Studies in some mammals and teleost medaka have revealed the outline of the central signaling pathway that leads to the PGR expression in the preovulatory follicles at ovulation. In this review, we summarize the current knowledge on what signaling mediators are involved in the LH-induced follicular expression of PGR at ovulation in these animals. LH-inducibility of follicular PGR expression is conserved. In both group of animals, activation of the LH receptor on the granulosa cell surface with LH commonly results in the increase of intracellular cAMP levels, while the downstream signaling cascades activated by high level of cAMP are totally different between mice and medaka. PGR is currently presumed to be induced via PKA/CREB-mediated transactivation and ERK1/2-dependent signaling in mice, but the receptor is induced via EPAC/RAP and AKT/CREB pathways in the teleost medaka. The differences and similarities in the signaling pathways for PGR expression between them is discussed from comparative and evolutionary aspects. We also discussed questions concerning PGR expression and its regulation needed to be investigated in future.


Assuntos
Oryzias , Receptores de Progesterona , Animais , Feminino , Células da Granulosa/metabolismo , Mamíferos/metabolismo , Camundongos , Oryzias/metabolismo , Ovulação/fisiologia , Congêneres da Progesterona , Progestinas/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Transdução de Sinais , Esteroides/metabolismo
8.
Gynecol Endocrinol ; 38(5): 398-402, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35238265

RESUMO

OBJECTIVE: To evaluate the different effects of a progestin-only contraceptive with desogestrel (DSG) vs combined oral contraceptives (COCs) for a first line long-term treatment of endometriosis-related pain among patients seeking hormonal contraception. METHODS: An observational retrospective cohort study was conducted in collaboration with a local outpatient clinic for endometriosis among a group of nulliparous young women (n = 216) with endometriosis-related pain and seeking contraception. The cohort was subdivided into a group (n = 73) treated as first line by DSG and another group (n = 75) treated by a COC. During the study, clinical symptoms, side effects and possible changes in OC type use were recorded. RESULTS: No significant difference was found between the two groups in terms of clinical characteristics and pain scores before treatment. After 6 months both treatments were effective in reducing endometriosis-related pain, and those treated with DSG showed lower levels of dysmenorrhea, dyspareunia and nonmenstrual pelvic pain than COCs group (p < .01). After 12 months, in DSG Group some patients (15%) switched from DSG to a COC for breakthrough bleeding, whereas in COC Group 48% of patients switched to another type of COC for reduced efficacy on pain and/or for side effects. After 3 years of OC treatment, in DSG Group 79% of patients maintained the same therapy, whereas in COC Group only 14% continued the same COC type, 37% switched to another COC and 47% to DSG. CONCLUSIONS: A progestin-only contraceptive with DSG is a valid option for long term management of endometriosis-related pain in patients seeking hormonal contraception.


Assuntos
Endometriose , Anticoncepção , Anticoncepcionais Orais Combinados/efeitos adversos , Desogestrel/efeitos adversos , Endometriose/complicações , Endometriose/tratamento farmacológico , Etinilestradiol/uso terapêutico , Feminino , Contracepção Hormonal , Humanos , Masculino , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Congêneres da Progesterona , Progestinas/uso terapêutico , Estudos Retrospectivos
9.
Minerva Obstet Gynecol ; 74(4): 364-376, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34180615

RESUMO

INTRODUCTION: In this paper, we report general pharmacological profile and major biological activities of natural progesterone (P) and progestins. The aim of this article consists of synthesizing the principal aspects of pharmacology and metabolism of P and progestins related to the clinical consequences of their use. EVIDENCE ACQUISITION: We review scientific literature on the topic "progestins," evaluating the most relevant data from original articles, reviews, and meta-analyses. EVIDENCE SYNTHESIS: Progestins represent a specific class of synthetic analogues of P clinically employed (alone or associated with estrogens) to manage several gynecological conditions, for instance multiple abortions, luteal phase defect, premenstrual syndrome, abnormal uterine bleeding, endometriosis, and menopause (for hormone replacement therapy). Besides their use in the field of contraception, many non-contraceptive benefits of estroprogestins are mostly due to the activities of progestins. Pharmacological characteristics, dosage and individual metabolism could be listed among the principal aspects influencing their clinical effects. CONCLUSIONS: The choice of each progestin according to its pharmacological profile is crucial for the appropriate management of any gynecological condition. An aware knowledge of these compounds is fundamental to hone medical practice.


Assuntos
Progesterona , Progestinas , Anticoncepção , Estrogênios/uso terapêutico , Feminino , Humanos , Gravidez , Progesterona/farmacologia , Congêneres da Progesterona/farmacologia , Progestinas/farmacologia
10.
Eur J Drug Metab Pharmacokinet ; 47(1): 49-56, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34635989

RESUMO

BACKGROUND AND OBJECTIVES: As the prevalence of some gynecological conditions depends on patient characteristics such as race/ethnicity, it is important to study therapies for these conditions in diverse populations. The study described in this article was conducted to investigate the safety, tolerability, and pharmacokinetics of vilaprisan, a selective progesterone receptor modulator, in Japanese women in Japan. It supplements two comparable studies that were conducted in healthy postmenopausal European and Chinese women, respectively. METHODS: In this exploratory randomized, placebo-controlled, double-blind, ascending-dose study, five groups of healthy postmenopausal Japanese women received vilaprisan as immediate-release tablets (1, 5, or 15 mg as a single dose or 1 or 5 mg/day for 28 days) or placebo tablets (single dosing: 8 subjects/dose step, thereof 2 subjects randomized to placebo; multiple dosing: 12 subjects/dose step, thereof 4 subjects randomized to placebo). Blood samples for pharmacokinetic profiles were collected over 14-19 days. Safety assessments were based on adverse event data, vital signs, electrocardiograms, clinical laboratory tests, and transvaginal ultrasound examinations. RESULTS: 48 participants were randomized, treated, and analyzed. Vilaprisan was rapidly absorbed, reaching maximum plasma concentrations (Cmax) between 1 and 3 h post dose. Post maximum, plasma concentrations rapidly declined, indicating pronounced distribution into tissues. The exposure of vilaprisan increased roughly dose-proportionally: The geometric mean (geometric coefficients of variation) areas under the concentration time curves from time zero to infinity (AUC∞) after single administration of 1, 5, or 15 mg vilaprisan were 67 µg·h/l (34%), 249 µg·h/l (15%), and 788 µg·h/l (37%), respectively. The AUC in the dosing interval after multiple administrations (AUC24,md) of 1 mg/day was 76 µg·h/l (59%), and the AUC24,md after 5 mg/day was 311 µg·h/l (20%). Geometric mean Cmax values also increased roughly dose-proportionally: They amounted to 6 µg/l (22%), 16 µg/l (33%), and 52 µg/l (27%) after single administration and to 8 µg/l (28%) and 31 µg/l (22%) after multiple administrations of the above doses. Mild adverse events were observed, similar to those observed in other clinical studies of vilaprisan. CONCLUSIONS: Overall, vilaprisan was safe and well tolerated. The exposure in Japanese women was similar to that observed in European and Chinese women in separate studies. TRIAL REGISTRATION: 15 Nov 2011 (no registration number assigned).


Assuntos
Pós-Menopausa , Congêneres da Progesterona/farmacocinética , Esteroides/farmacocinética , Administração Oral , Idoso , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Congêneres da Progesterona/administração & dosagem , Congêneres da Progesterona/sangue , Receptores de Progesterona/metabolismo , Esteroides/administração & dosagem , Esteroides/sangue
11.
Biomolecules ; 11(11)2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34827682

RESUMO

Ovarian sex steroids can modulate new vessel formation and development, and the clarification of the underlying mechanism will provide insight into neovascularization-related physiological changes and pathological conditions. Unlike estrogen, which mainly promotes neovascularization through activating classic post-receptor signaling pathways, progesterone (P4) regulates a variety of downstream factors with angiogenic or antiangiogenic effects, exerting various influences on neovascularization. Furthermore, diverse progestins, the synthetic progesterone receptor (PR) agonists structurally related to P4, have been used in numerous studies, which could contribute to unequal actions. As a result, there have been many conflicting observations in the past, making it difficult for researchers to define the exact role of progestogens (PR agonists including naturally occurring P4 and synthetic progestins). This review summarizes available evidence for progestogen-mediated neovascularization under physiological and pathological circumstances, and attempts to elaborate their functional characteristics and regulatory patterns from a comprehensive perspective.


Assuntos
Progestinas , Progesterona , Congêneres da Progesterona
12.
Environ Sci Pollut Res Int ; 28(36): 50245-50254, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33956318

RESUMO

The endocrine-disrupting activities of UV filters and synthetic progestin have raised concerns about their adverse risks. In this study, 208 urine samples were collected from Shanghai residents for the determination of seven benzophenones (BPs) and six synthetic progestins. The highest median concentration (6.21ng g-1 Cr) was observed in young adults (21-50 years), followed by a concentration of 3.86 ng g-1 Cr in elderly adults (over 50 years old), and the lowest median concentration (1.32 ng g-1 Cr) was found in children (8-11 years old). The detection rates of BP-3 and EE2 in adults were 97% and 82%, and in children were 31% and 24%, respectively. Synthetic progestin levels in Shanghai, China, were relatively low compared to other countries. And the urinary BPs level showed an increasing trend in Chinese in the past 5 years. The principal component analysis suggested that adults' exposure to BP-1 and BP-3 was related, which occurs through food or dermal absorption of these chemicals present in cosmetic products and coatings. And diet was an important exposure pathway for children exposed to BPs. Despite relatively high levels of synthetic progestin for female and obese, the total estimated daily intake (EDI) was still lower than acceptable daily intake adopted by America. In the Monte-Carlo analysis, the 95th percentile of hazard quotients (HQs) was 0.83, which indicated that potential health risks were appreciated in the studied population.


Assuntos
Benzofenonas , Cosméticos , Idoso , Benzofenonas/análise , Criança , China , Exposição Ambiental/análise , Feminino , Humanos , Pessoa de Meia-Idade , Congêneres da Progesterona , Protetores Solares/análise , Adulto Jovem
13.
Gynecol Endocrinol ; 37(7): 646-649, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33749482

RESUMO

PURPOSE: Estradiol valerate/nomegestrol acetate (E2V/NOMAC) is a new combined oral contraceptive with a good tolerability profile and low drop-out rates, which was shown to improve menstrual-related symptoms. This study aims to evaluate its effectiveness in the control of symptoms and progression of disease in women with ovarian endomestriomas and deep infiltrating endometriosis (DIE). METHODS: This was a retrospective cohort study on 39 women with pelvic endometriosis treated with E2V/NOMAC. We assessed for each patient, at the beginning of treatment and after 6 months, the painful symptoms, through a global VAS (Visual Analogue Scale) index and the size of the greatest ovarian and/or deep infiltrating endometriotic lesions. RESULTS: After 6 months of treatment, a significant reduction was observed for the global VAS score for pain symptoms and for the mean size of ovarian endometriomas, whereas DIE lesions did not present significant changes in mean size. CONCLUSIONS: E2/NOMAC was effective in reducing pain symptoms associated with pelvic endometriosis and the size of ovarian endometriomas, whereas DIE lesions remained stable. This therapy could provide good results in the control of symptoms and disease progression in women with pelvic endometriosis.


Assuntos
Anticoncepcionais Orais Combinados/uso terapêutico , Endometriose/tratamento farmacológico , Estradiol/uso terapêutico , Estrogênios/uso terapêutico , Megestrol/uso terapêutico , Norpregnadienos/uso terapêutico , Doenças Ovarianas/tratamento farmacológico , Dor Pélvica/fisiopatologia , Congêneres da Progesterona/uso terapêutico , Adulto , Estudos de Coortes , Combinação de Medicamentos , Endometriose/diagnóstico por imagem , Endometriose/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Doenças Ovarianas/diagnóstico por imagem , Doenças Ovarianas/fisiopatologia , Medição da Dor , Estudos Retrospectivos , Ultrassonografia , Adulto Jovem
14.
Sci Total Environ ; 751: 141766, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32889472

RESUMO

The occurrence of biologically potent sex hormones in agricultural soils is of growing concern due to their ability to disrupt the endocrine systems of aquatic organisms after being transported to surface waters via runoff. This study, therefore, examined the large-scale occurrence of 34 natural and synthetic sex hormones (13 progestins, 16 androgens, and 5 estrogens) in soils from 7 provinces and 1 municipality in China. The target sex hormones were detected in 99.3% of the soil samples, indicating their widespread occurrence in most agricultural areas. Additionally, seven synthetic progestins were detected in soils for the first time. The total concentration of the 34 sex hormones (Σsex hormones) in the sampled soils ranged from below the method detection limit to 23.7 ng/g (mean of 4.72 ± 4.07 ng/g), with androgens and progestins being the most dominant hormone groups. Significant correlations were observed among the concentrations of Σestrogens, Σandrogens, and Σprogestins (r = 0.117-0.433, p < 0.001), suggesting similar sources of sex hormones. The mean concentration of Σsex hormones varied considerably across the selected provinces/municipality. Notably, the annual slaughter of poultry and swine (R2 = 0.75-0.88), female population (R2 = 0.57-0.58), and soil organic carbon content (R2 = 0.20-0.55) in each province were significantly correlated with the concentrations or mean concentrations of Σsex hormones, Σestrogens, or Σprogestins. This finding implies that these parameters contributed to the occurrence and distribution of sex hormones in the studied soils. Finally, risk quotients for some sex hormones exceeded 0.01, indicating medium or high risks to agroecosystems. This study highlights the importance of designing an optimal manure fertilization strategy in order to mitigate the risks posed by sex hormones in agroecosystems.


Assuntos
Androgênios , Poluentes do Solo , Androgênios/análise , Animais , Carbono , China , Monitoramento Ambiental , Estrogênios/análise , Congêneres da Progesterona , Progestinas/análise , Solo , Poluentes do Solo/análise , Suínos
15.
Front Endocrinol (Lausanne) ; 12: 781066, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34975755

RESUMO

There is a steady global rise in the use of progestin subdermal implants, where use has increased by more than 20 times in the past two decades. BC risk has been reported with the older progestin only methods such as oral pills, injectables, and intrauterine devices, however, little is known about the risk with subdermal implants. In this review, we aim to update clinicians and researchers on the current evidence to support patient counseling and to inform future research directions. The available evidence of the association between the use of progestin subdermal implants and BC risk is discussed. We provide an overview of the potential role of endogenous progesterone in BC development. The chemical structure and molecular targets of synthetic progestins of relevance are summarized together with the preclinical and clinical evidence on their association with BC risk. We review all studies that investigated the action of the specific progestins included in subdermal implants. As well, we discuss the potential effect of the use of subdermal implants in women at increased BC risk, including carriers of BC susceptibility genetic mutations.


Assuntos
Neoplasias da Mama/induzido quimicamente , Anticoncepcionais Femininos/efeitos adversos , Implantes de Medicamento/efeitos adversos , Educação de Pacientes como Assunto/métodos , Congêneres da Progesterona/efeitos adversos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Ensaios Clínicos como Assunto/métodos , Anticoncepcionais Femininos/administração & dosagem , Implantes de Medicamento/administração & dosagem , Feminino , Humanos , Congêneres da Progesterona/administração & dosagem , Progestinas/administração & dosagem , Progestinas/efeitos adversos , Fatores de Risco
17.
Biochem Biophys Res Commun ; 533(4): 1027-1033, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33012509

RESUMO

Antiretroviral therapy has slowed the HIV/AIDS pandemic and is currently being used as a prophylactic measure for individuals at high risk of infection. However, concerns over adverse effects of long-term use need to be explored. We hypothesize that this may occur, at least in part, through off-target effects via select steroid receptors (SRs) that broadly regulate multiple physiological processes. We investigated the effects of maraviroc (MVC), tenofovir disoproxil fumarate (TDF), and dapivirine (DPV) on progesterone receptor B (PR-B) transcriptional activity. We found that MVC and TDF activate PR-B transcription in the absence of progestogens on a PR-regulated promoter reporter construct and on endogenous PR-regulated genes. MVC and TDF exhibited no direct binding to PR-B; however, increased PR-B phosphorylation was detected with TDF but not MVC. DPV transactivated gilz and ptgs2 in the absence of progestogens and exhibited PR-B binding while showing no effects on phosphorylation, suggesting that it may activate PR-B through a direct mechanism. Our study shows that potential off-target immunomodulatory effects of MVC, TDF and DPV occur in vitro and these are most likely mediated by different mechanisms of PR-B activation.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Maraviroc/efeitos adversos , Pirimidinas/efeitos adversos , Receptores de Progesterona/agonistas , Tenofovir/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Ligação Competitiva , Linhagem Celular , Contraceptivos Hormonais/farmacocinética , Contraceptivos Hormonais/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1 , Humanos , Fatores Imunológicos/efeitos adversos , Técnicas In Vitro , Levanogestrel/farmacocinética , Levanogestrel/farmacologia , Maraviroc/farmacocinética , Fosforilação , Congêneres da Progesterona/farmacocinética , Congêneres da Progesterona/farmacologia , Pirimidinas/farmacocinética , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Tenofovir/farmacocinética , Ativação Transcricional/efeitos dos fármacos
18.
Am J Surg Pathol ; 44(10): 1429-1439, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32931681

RESUMO

BACKGROUND: Conservative management with progestin is a treatment option for atypical hyperplasia (AH). However, pathologic diagnosis of residual/recurrent lesions is often problematic because of the profound morphologic changes induced by progestin and the lack of established diagnostic criteria for progestin-treated residual AH. METHODS: We conducted a longitudinal study of 265 endometrial biopsies from 54 patients with a history of AH on progestin therapy. Patient outcomes were divided into 3 categories after morphologic review and immunohistochemical staining with phosphatase and tensin homolog (PTEN) and paired box 2 (PAX2): (1) persistent or residual disease; (2) recurrent disease; (3) complete response. All specimens were classified into 3 categories based on morphology: (1) persistent/recurrent disease (nonresponse), (2) morphologically uncertain response, (3) optimally treated (complete response). The staining patterns of PTEN/PAX2 were tracked over time in individual patients and correlated with morphologic findings before and after progestin therapy. RESULTS: Our data showed that aberrant expression patterns of PTEN and/or PAX2 were identified in 48 (88.9%) of the 54 primary biopsies and persisted in persistent/recurrent AH across serial endometrial biopsies (n=99, P<0.00001), while normal PTEN and PAX2 expressions were consistently observed in optimally treated cases (n=84, P<0.00001). More importantly, follow-up biopsies that showed a morphologically uncertain response but a PTEN/PAX2 expression pattern identical to the initial biopsy were significantly correlated with persistent or recurrent disease (n=18, P=0.000182), as evidenced by areas with morphologic features diagnostic of AH on subsequent biopsy. CONCLUSIONS: Biomarker PTEN/PAX2 signatures offer a valuable diagnostic aid to identify residual AH in progestin-treated endometrial samples for which the biomarker status from preprogestin treated AH is known. The findings of this study are promising for a possible future change of diagnostic practice.


Assuntos
Biomarcadores Tumorais/análise , Hiperplasia Endometrial/diagnóstico , Hiperplasia Endometrial/tratamento farmacológico , Endométrio/efeitos dos fármacos , Congêneres da Progesterona/uso terapêutico , Adulto , Idoso , Biomarcadores/análise , Endométrio/patologia , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Fator de Transcrição PAX2/análise , PTEN Fosfo-Hidrolase/análise , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/tratamento farmacológico , Recidiva
19.
Fertil Steril ; 114(2): 191-199, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32741458

RESUMO

The current ovarian cycle paradigm postulates that ovulation is triggered by a critically sustained elevation of estradiol. However, an in-depth look into the published data reveals considerable uncertainty about the relative roles of progesterone and estradiol in the ovulation process.This review provides compelling evidences that the role of estradiol in ovulation has been misinterpreted and that the true physiological trigger of ovulation is a luteinizing hormone-independent preovulatory progesterone surge in the circulation to approximately 0.5 ng/mL. Furthermore, the current work reconciles the ability of progesterone to trigger ovulation, with its well-established ability to block ovulation during pregnancy, or when administered in the form of a synthetic progestin in birth control formulations and with experimental data that estradiol benzoate triggers ovulation in the complete absence of progesterone.


Assuntos
Gonadotropinas/sangue , Hipotálamo/metabolismo , Hormônio Luteinizante/sangue , Ciclo Menstrual/sangue , Ovário/metabolismo , Ovulação/sangue , Progesterona/sangue , Contraceptivos Hormonais/farmacologia , Estradiol/análogos & derivados , Estradiol/sangue , Estradiol/metabolismo , Estradiol/farmacologia , Feminino , Humanos , Ciclo Menstrual/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Congêneres da Progesterona/farmacologia , Transdução de Sinais
20.
Acta Obstet Gynecol Scand ; 99(11): 1554-1560, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32609875

RESUMO

INTRODUCTION: Transcervical resection of the endometrium (TCRE) is a first-line surgical treatment of abnormal uterine bleeding. However, many women experience unsuccessful results, causing hysterectomy in up 17% of cases. The aim of this study was to describe the odds of hysterectomy in women with abnormal uterine bleeding, treated with TCRE and levonorgestrel intrauterine contraceptive device (TCRE + LNG-IUCD) or TCRE alone. The secondary aim was to analyze the rate of amenorrhea. MATERIAL AND METHODS: Designed as a retrospective cohort study, and conducted at Odense University Hospital, Denmark, the study included women with abnormal uterine bleeding, who underwent TCRE from January 2013 to December 2015. The decision of treatment with respect to LNG-IUCD was at the woman's discretion. Data were collected from medical records and a self-reported retrospective bleeding-pattern questionnaire. A multivariate regression model was used, enabling adjustment for potential and identified confounders. RESULTS: Out of 432 women, 276 (62%) consented to inclusion and of these, 16 (4%) were excluded. In total 88 (34%) received combined treatment and 172 (66%) received TCRE alone. Ten women (11%) treated with TCRE + LNG-IUCD underwent hysterectomy, compared with 27 (16%) treated with TCRE alone (OR = 0.69, 95% CI 0.28-1.56; P = .34). Multivariate analysis disclosed a significant effect of TCRE + LNG-IUCD (OR = 0.35, 95% CI 0.13-0.97; P = .04) on hysterectomy. The presence of fibromas was shown to increase the odds of treatment failure, resulting in hysterectomy (OR 2.69, 95% CI 1.15-6.31; P = .02). Furthermore, the incidence of amenorrhea was 59% in the TCRE + LNG-IUCD group and 36% in the TCRE alone group (OR = 2.56, 95% CI 1.46-4.49; P < .01). CONCLUSIONS: The study showed significantly lower odds of hysterectomy in the TCRE + LNG-IUCD group when adjusted for confounders. Combination treatment improves the bleeding patterns significantly compared with monotherapy with TCRE.


Assuntos
Contraceptivos Hormonais/uso terapêutico , Técnicas de Ablação Endometrial/estatística & dados numéricos , Endométrio/cirurgia , Dispositivos Intrauterinos Medicados/estatística & dados numéricos , Menorragia/terapia , Estudos de Coortes , Terapia Combinada , Dinamarca , Feminino , Humanos , Histerectomia/estatística & dados numéricos , Levanogestrel/uso terapêutico , Menorragia/tratamento farmacológico , Menorragia/cirurgia , Pessoa de Meia-Idade , Progesterona/uso terapêutico , Congêneres da Progesterona/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
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