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Acta Obstetricia Et Gynecologica... Nov 2015The aim of this article is to review the physiology of progesterone and focus on its physiological actions on tissues such as endometrium, uterus, mammary gland,... (Review)
Review
INTRODUCTION
The aim of this article is to review the physiology of progesterone and focus on its physiological actions on tissues such as endometrium, uterus, mammary gland, cardiovascular system, central nervous system and bones. In the last decades, the interest of researchers has focused on the role of progesterone in genomic and non-genomic receptor mechanisms.
MATERIALS AND METHODS
We searched PubMed up to December 2014 for publications on progesterone/steroidogenesis.
RESULTS AND CONCLUSIONS
A better understanding of the biological genomic and non-genomic receptor mechanisms could enable us in the near future to obtain a more comprehensive knowledge of the safety and efficacy of this agent during hormone replacement therapy (natural progesterone), in vitro fertilization (water-soluble subcutaneous progesterone), in traumatic brain injury, Alzheimer's disease and diabetic neuropathy, even though further clinical studies are needed to prove its usefulness.
Topics: Cell Membrane; Cell Nucleus; Central Nervous System; Embryo Implantation; Endometrium; Female; Humans; Mammary Glands, Human; Menstrual Cycle; Osteoporosis; Progesterone; Receptors, Progesterone
PubMed: 26358238
DOI: 10.1111/aogs.12771 -
Pathology Oncology Research : POR Jan 2020Rapid advance in oncology leads to increasing survival of oncologic patients. More and more of them live long enough to reach either the natural age of menopause or, as... (Review)
Review
Rapid advance in oncology leads to increasing survival of oncologic patients. More and more of them live long enough to reach either the natural age of menopause or, as a side effect of their oncotherapy, experience the cessation of gonadal function, leading to premature ovarian insufficiency, with disturbing vasomotor symtoms and long-term negative cardiovascular and skeletal effects. Thus, an ever increasing number of cancer survivors search endocrinologic help in the form of hormone replacement therapy (HRT). The misinterpretation of the WHI (Women's Health Initiative) Study has lead to an irrational fear of female hormone replacement, both by the general population and medical professionals. It has seemed the logical and safe conclusion to many physicians to avoid HRT, supposing that this attitude definitely causes no harm, whereas the decision of prescribing estrogen alone or with progestins might bear oncologic and thromboembolic risks and may even lead to litigation in case of a potentially related complication. However, it was known even before the WHI results that premature menopause and hypogonadism decreases the life expectancy of women by years through its skeletal and cardiovascular effects, and this negative effect correlates with the length of the hypoestrogenaemic period. Therefore, the denial of HRT also needs to be supported by evidence and should be weighed againts the risks of HRT. Yet, the oncologic risk of HRT is extremely difficult to assess. In this work we review the latest evidence from in vitro experiments to clinical studies, regarding HRT in survivors of gynecologic and non-gynecologic cancers. Based on our literature research, we group tumours regarding the oncologic risk of properly chosen female hormone replacement therapy in cancer survivors as follows: 'HRT is advanageous' (e.g. endometrial cancer type I, cervical adenocarcinoma, haematologic malignancies, local cutaneous malignant melanoma, colorectal cancer, hepatocellular cancer); 'HRT is neutral' (e.g. BRCA 1/2 mutation carriers without cancer, endometrial cancer type II, uterinal carcinosarcoma and adenosarcoma, certain types of ovarian cancer, cervical, vaginal and vulvar squamous cell carcinoma, prolactinoma, kidney cancer, pancreatic cancer, thyroid cancer); 'HRT is relatively contraindicated' for various reasons (e.g. leiomyosarcoma, certain types of ovarian tumours, brain tumours, advanced metastatic malignant melanoma, lung cancer, gastric cancer, bladder cancer); 'HRT is diasadvantageous and thus contraindicated' (e.g. breast cancer, endometrial stroma sarcoma, meningioma, glioma, hormone receptor positive gastric and bladder cancer).
Topics: Breast Neoplasms; Cancer Survivors; Estrogens; Female; Genital Neoplasms, Female; Hormone Replacement Therapy; Humans; Neoplasms; Neoplasms, Second Primary; Progesterone
PubMed: 30617760
DOI: 10.1007/s12253-018-00569-x -
International Journal of Molecular... Jul 2022Progesterone is a steroid hormone traditionally linked with female fertility and pregnancy. In current reproductive medicine, progesterone and its analogues play crucial... (Review)
Review
Progesterone is a steroid hormone traditionally linked with female fertility and pregnancy. In current reproductive medicine, progesterone and its analogues play crucial roles. While the discovery of its effects has a long history, over recent decades, various novel actions of this interesting steroid have been documented, of which its neuro- and immunoprotective activities are the most widely discussed. Discoveries of the novel biological activities of progesterone have also driven research and development in the field of progesterone analogues used in human medicine. Progestogen treatment has traditionally and predominately been used in maintaining pregnancy, the prevention of preterm labor, various gynecological pathologies, and in lowering the negative effects of menopause. However, there are also various other medical fields where progesterone and its analogues could find application in the future. The aim of this work is to show the mechanisms of action of progesterone and its metabolites, the physiological and pharmacological actions of progesterone and its synthetic analogues in human medicine, as well as the impacts of its production and use on the environment.
Topics: Female; Hormones; Humans; Infant, Newborn; Pregnancy; Progesterone; Progestins
PubMed: 35887338
DOI: 10.3390/ijms23147989 -
Climacteric : the Journal of the... Aug 2018Progesterone is a neurosteroid and a neuroactive steroid, produced primarily by the corpus luteum and the placenta. In some animal models, progesterone affects cognitive... (Review)
Review
Progesterone is a neurosteroid and a neuroactive steroid, produced primarily by the corpus luteum and the placenta. In some animal models, progesterone affects cognitive performance, and its potential role in human cognition is especially germane to women. This role can be investigated through associations between peripheral concentrations of progesterone in blood or saliva and neuropsychological test results, through differences in cognitive profiles between women using menopausal hormone therapy with and without a progestogen, and through clinical trials. In naturally cycling reproductive-age women and pregnant women, there is no consistent relation between progesterone levels and cognition. In postmenopausal women within 6 years of menopause and not using hormone therapy, progesterone levels are positively associated with verbal memory and global cognition, but reported associations in older postmenopausal women are null. Some observational studies of postmenopausal women using hormone therapy raise concern of a small deleterious cognitive effect of progestogen (medroxyprogesterone acetate was most often reported in these studies), but this association may due to confounding factors. Small, short-term clinical trials of progesterone show no meaningful effect on cognition. The quality of evidence is low, but overall findings do not reveal consistent, clinically important effects of progesterone on cognitive function in women.
Topics: Animals; Cognition; Cognition Disorders; Estrogen Replacement Therapy; Female; Humans; Medroxyprogesterone Acetate; Memory; Neuropsychological Tests; Postmenopause; Pregnancy; Progesterone; Progestins; Randomized Controlled Trials as Topic
PubMed: 29852783
DOI: 10.1080/13697137.2018.1476484 -
Lancet (London, England) Mar 2021Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Preterm birth is a global health priority. Using a progestogen during high-risk pregnancy could reduce preterm birth and adverse neonatal outcomes.
METHODS
We did a systematic review of randomised trials comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth. We identified published and unpublished trials that completed primary data collection before July 30, 2016, (12 months before data collection began), by searching MEDLINE, Embase, CINAHL, the Maternity and Infant Care Database, and relevant trial registers between inception and July 30, 2019. Trials of progestogen to prevent early miscarriage or immediately-threatened preterm birth were excluded. Individual participant data were requested from investigators of eligible trials. Outcomes included preterm birth, early preterm birth, and mid-trimester birth. Adverse neonatal sequelae associated with early births were assessed using a composite of serious neonatal complications, and individually. Adverse maternal outcomes were investigated as a composite and individually. Individual participant data were checked and risk of bias assessed independently by two researchers. Primary meta-analyses used one-stage generalised linear mixed models that incorporated random effects to allow for heterogeneity across trials. This meta-analysis is registered with PROSPERO, CRD42017068299.
FINDINGS
Initial searches identified 47 eligible trials. Individual participant data were available for 30 of these trials. An additional trial was later included in a targeted update. Data were therefore available from a total of 31 trials (11 644 women and 16185 offspring). Trials in singleton pregnancies included mostly women with previous spontaneous preterm birth or short cervix. Preterm birth before 34 weeks was reduced in such women who received vaginal progesterone (nine trials, 3769 women; relative risk [RR] 0·78, 95% CI 0·68-0·90), 17-OHPC (five trials, 3053 women; 0·83, 0·68-1·01), and oral progesterone (two trials, 181 women; 0·60, 0·40-0·90). Results for other birth and neonatal outcomes were consistently favourable, but less certain. A possible increase in maternal complications was suggested, but this was uncertain. We identified no consistent evidence of treatment interaction with any participant characteristics examined, although analyses within subpopulations questioned efficacy in women who did not have a short cervix. Trials in multifetal pregnancies mostly included women without additional risk factors. For twins, vaginal progesterone did not reduce preterm birth before 34 weeks (eight trials, 2046 women: RR 1·01, 95% CI 0·84-1·20) nor did 17-OHPC for twins or triplets (eight trials, 2253 women: 1·04, 0·92-1·18). Preterm premature rupture of membranes was increased with 17-OHPC exposure in multifetal gestations (rupture <34 weeks RR 1·59, 95% CI 1·15-2·22), but we found no consistent evidence of benefit or harm for other outcomes with either vaginal progesterone or 17-OHPC.
INTERPRETATION
Vaginal progesterone and 17-OHPC both reduced birth before 34 weeks' gestation in high-risk singleton pregnancies. Given increased underlying risk, absolute risk reduction is greater for women with a short cervix, hence treatment might be most useful for these women. Evidence for oral progesterone is insufficient to support its use. Shared decision making with woman with high-risk singleton pregnancies should discuss an individual's risk, potential benefits, harms and practicalities of intervention. Treatment of unselected multifetal pregnancies with a progestogen is not supported by the evidence.
FUNDING
Patient-Centered Outcomes Research Institute.
Topics: 17-alpha-Hydroxyprogesterone; Administration, Intravaginal; Decision Making, Shared; Female; Humans; Infant, Newborn; Injections, Intramuscular; Pregnancy; Pregnancy Outcome; Pregnancy, High-Risk; Premature Birth; Progesterone; Randomized Controlled Trials as Topic; Risk Assessment
PubMed: 33773630
DOI: 10.1016/S0140-6736(21)00217-8 -
Best Practice & Research. Clinical... Nov 2020Mood and anxiety disorders are vastly overrepresented in women, and one important contributor to these differences is the fluctuation in sex steroids in women during the... (Review)
Review
Mood and anxiety disorders are vastly overrepresented in women, and one important contributor to these differences is the fluctuation in sex steroids in women during the reproductive years. Considerable evidence supports a role for abnormal sensitivity to these hormonal fluctuations for some women, who develop mood symptoms associated with reproductive transitions. This chapter presents evidence of the role of endogenous progesterone and its metabolites in such mood symptoms, and then goes on to cover the evidence concerning exogenous progesterone's effects on mood. Overall, the literature does not support an association between exogenous progesterone and negative mood in the general population, but does indicate that subset of women may be vulnerable to such effects. Research is lacking on women with psychiatric illness.
Topics: Affect; Female; Humans; Mood Disorders; Progesterone; Reproduction
PubMed: 32723604
DOI: 10.1016/j.bpobgyn.2020.06.001 -
Hormones and Behavior Feb 2013Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental model. And while estrogen intervention in... (Review)
Review
Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental model. And while estrogen intervention in these animals has, at least partially, restored cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal models and in humans. Here, we review the evidence that supports the neuroprotective effects of progesterone and discuss the various mechanisms that are thought to mediate these protective effects. We also discuss the receptor pharmacology of progesterone's neuroprotective effects and present a conceptual model of progesterone action that supports the complementary effects of membrane-associated and classical intracellular progesterone receptors. In addition, we discuss fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin, medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain function.
Topics: Animals; Brain; Cognition; Cytoprotection; Humans; Neuroprotective Agents; Progesterone; Progesterone Congeners; Receptors, Progesterone
PubMed: 22732134
DOI: 10.1016/j.yhbeh.2012.06.003 -
American Journal of Obstetrics and... Jan 2021In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy.
OBJECTIVE
The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24 and 33 weeks.
STUDY DESIGN
The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24 and 33 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24 and 33 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth.
RESULTS
We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24 and 33 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20-1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69).
CONCLUSION
In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24 and 33 weeks' gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm.
Topics: Administration, Intravaginal; Adult; Double-Blind Method; Europe; Female; Humans; Pregnancy; Pregnancy Trimesters; Pregnancy, Twin; Premature Birth; Prenatal Care; Progesterone; Treatment Outcome
PubMed: 32598909
DOI: 10.1016/j.ajog.2020.06.050 -
Health Technology Assessment... May 2016Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a... (Randomized Controlled Trial)
Randomized Controlled Trial
PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation.
BACKGROUND AND OBJECTIVES
Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted.
DESIGN AND SETTING
A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites).
PARTICIPANTS AND INTERVENTIONS
Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks).
MAIN OUTCOME MEASURES
Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.
METHODS
Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth.
RESULTS
A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341.
CONCLUSIONS
There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM.
LIMITATIONS
This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle.
FUTURE WORK
Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM.
TRIAL REGISTRATION
Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44.
FUNDING
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.
Topics: Abortion, Habitual; Administration, Intravaginal; Adolescent; Adult; Congenital Abnormalities; Cost-Benefit Analysis; Double-Blind Method; Female; Gestational Age; Humans; Infant; Infant Mortality; Netherlands; Pregnancy; Pregnancy Outcome; Pregnancy Trimester, First; Progesterone; Quality-Adjusted Life Years; United Kingdom; Young Adult
PubMed: 27225013
DOI: 10.3310/hta20410 -
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