Effects Of Progestins Research Articles

Meta-analysis and randomized controlled studies: what clinicists should know to prevent regular and spontaneous miscarriages of unexplained genesis?

The etiopathology of recurrent miscarriage is a combination of various factors, including chromosomal defects, genetic or structural abnormalities, endocrine abnormalities, infections, immune dysfunction, thrombophilia disorders, antiphospholipid syndrome, and unexplained causes.It has long been known that progesterone is needed to maintain pregnancy and its physiological development. Insufficient progesterone secretion and its low level in the blood serum in early pregnancy is associated with the threat of miscarriage and loss of pregnancy at a later stage – up to 16 weeks of gestation. The effectiveness of the vaginal micronized progesterone (VMP) at a dose of 400 mg twice a day in the first trimester of pregnancy was evaluated in two recent large high-quality multicenter placebo-controlled studies, one of which included pregnant women with recurrent miscarriages of unexplained origin (PROMISE Trial), and the other study included women with early pregnancy loss (PRISM Trial). A key finding, pioneered in the PROMISE study and later confirmed in the PRISM study, was that VMP treatment associated with an increase in live births in line with the number of previous miscarriages. It has been shown that there is no evidence regarding safety concerns with natural micronized progesterone. Treatment with an VMP should be recommended for women with bleeding in early pregnancy and a history of one or more miscarriages. The recommended treatment regimen is 400 mg 2 times a day (800 mg/day) intravaginal, starting from the moment bleeding is detected up to 16 weeks of pregnancy.In the future, there remains uncertainty effectiveness and safety of alternative progestogens (dydrogesterone) for the treatment of women at high risk of threatened abortion and recurrent miscarriage. It is important that dydrogesterone is a synthetic progestin, its structure is significantly different from natural progesterone, and therefore it is necessary to unequivocally prove the short- and long-term safety of this drug before considering its use in clinical practice.

Progestins as Anticancer Drugs and Chemosensitizers, New Targets and Applications

Progesterone and its synthetic analogues, progestins, participate in the regulation of cell differentiation, proliferation and cell cycle progression. Progestins are usually applied for contraception, maintenance of pregnancy, and hormone replacement therapy. Recently, their effectiveness in the treatment of hormone-sensitive tumors was revealed. According to current data, the anticancer activity of progestins is mainly mediated by their cytotoxic and chemosensitizing influence on different cancer cells. In connection with the detection of previously unknown targets of the progestin action, which include the membrane-associated progesterone receptor (PR), non-specific transporters related to the multidrug resistance (MDR) and mitochondrial permeability transition pore (MPTP), and checkpoints of different signaling pathways, new aspects of their application have emerged. It is likely that the favorable influence of progestins is predominantly associated with the modulation of expression and activity of MDR-related proteins, the inhibition of survival signaling pathways, especially TGF-β and Wnt/β-catenin pathways, which activate the proliferation and promote MDR in cancer cells, and the facilitation of mitochondrial-dependent apoptosis. Biological effects of progestins are mediated by the inhibition of these signaling pathways, as well as the direct interaction with the nucleotide-binding domain of ABC-transporters and mitochondrial adenylate translocase as an MPTP component. In these ways, progestins can restore the proliferative balance, the ability for apoptosis, and chemosensitivity to drugs, which is especially important for hormone-dependent tumors associated with estrogen stress, epithelial-to-mesenchymal transition, and drug resistance.

Effects of menopausal hormone therapy on ambulatory blood pressure and arterial stiffness in postmenopausal Korean women with grade 1 hypertension: a randomized, placebo-controlled trial

BackgroundEstrogen therapy in early menopausal women decreases the risk of coronary heart disease and parenteral, but not oral, estrogen is reported to reduce blood pressure (BP). Progestogens are typically added to estrogens to prevent unopposed endometrial stimulation. The effects of progestogen on BP have been less well studied to date. This study was conducted to explore the impacts of micronized progesterone (MP4) combined with percutaneous estradiol gel (PEG) on hemodynamics in postmenopausal Korean women with grade 1 hypertension.MethodsFifty-two postmenopausal women (aged 49–75 years) with systolic BP (SBP) of 140–160 mmHg or diastolic BP (DBP) of 90–100 mmHg were randomly assigned for 12 weeks to placebo (n = 16), estrogen therapy (ET) (n = 19) with PEG (0.1 %, 1 g./d), or estrogen + progestogen therapy (EPT, n = 17) with PEG and MP4 (100 mg/d). The primary endpoint was ambulatory BP and the secondary endpoints were arterial stiffness as brachial–ankle pulse-wave velocity (baPWV) and aortic parameters on applanation tonometry.ResultsOne woman in the ET group dropped out, so 51 participants were finally analyzed. Outcome measures for ambulatory BP and arterial stiffness were not different between groups. Within-group comparisons showed that EPT significantly decreased daytime heart rate and baPWV: the changes from baseline (mean ± standard deviation) were − 2.5 ± 5.7 bpm (P = 0.03) and − 0.6 ± 1.4 m/s (P = 0.04), respectively. After adjusting for baseline, linear regression analysis revealed a significant difference in the relationship between baseline and 12-week baPWV among groups (P = 0.02). The relationship was significantly different between placebo and ET (P = 0.03) and EPT (P = 0.01), respectively, but not between ET and EPT. Additionally, pooled results of active treatments disclosed that SBP, DBP, PWV, and augmentation index at the aorta were significantly reduced relative to baseline.ConclusionsThere was no difference in ambulatory BP between ET and EPT in postmenopausal Korean women with grade 1 hypertension. Further, ET and EPT similarly decreased baPWV from baseline as compared with placebo. MP4 might not adversely influence estrogen effects on ambulatory BP and arterial stiffness.Trial registrationClinical Research Information Registry, KCT0005405, Registered 22 September 2020 - Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do?all_type=Y&search_page=L&pageSize=10&page=1&seq=17608&search_lang=E.

Current Knowledge of Progestin-Only Pills

Since the 1960s, contraceptive pills have been at the service of humanity. They are one of the innovations that have contributed the most to the changing role of women in society and to women achieving the role they play today. Combined oral contraceptives (COCs) opened up opportunities to increase knowledge about the effects of estrogens and progestins in the female organism. The overall results of this evolution were progestin-only contraceptives in general and estrogen-free oral contraceptives as progestin-only pills (POPs) in particular. To identify the position currently held by POPs, a bibliographic review was carried out in the following databases: PubMed, ScienceDirect, EBSCOhost, OvidSP, Embase, and SciELO in Spanish. POPs have evolved notably from restricted use only during breastfeeding to a broader context. The absence of estrogen in the pill currently offers more advantages than disadvantages. The recent introduction of POP containing 4.0 mg of drospirenone, administered in a 24/4-day regimen, offers better cycle control than previous POPs, as it allows much more predictable bleedings and the same contraceptive efficacy as COCs. Hormonal contraception use continues to grow. The options to regulate reproduction are numerous, and users have a greater number of options to choose the one that suits their needs and comforts. Health professionals must provide high-quality contraceptive counseling, offering all available tools, including POPs.

Progestin significantly inhibits carcinogenesis in the mogp-TAg mouse model of fallopian tube cancer

<h3>Objectives:</h3> Recent studies suggest the fallopian tube epithelium (FTE) harbors the precursor for high grade ovarian cancer (HGSC), creating opportunities for targeting the FTE for ovarian cancer prevention. Preclinical evidence supports progestins as ovarian cancer preventives, but the effect of progestins on the FTE has not been well characterized. <i>in vitro</i> and primate models suggest that progestins clear genetically damaged cells in the ovarian epithelium and endometrium by activating molecular pathway such as apoptosis. The mogp-TAg transgenic mouse develops neoplastic lesions such as p53 signatures and serous tubal intraepithelial carcinoma (STIC) in the fallopian tube (FT) in a similar manner to that described in human fallopian and ovarian cancers. In this study, we investigated the inhibitory effects of the progestin-Depo-medroxyprogesterone acetate (DMPA) on FT carcinogenesis in the mogp-TAg mouse. <h3>Methods:</h3> Mogp-TAg mice (10 per group) at 5 weeks of age were injected with vehicle or the progestin Depo-medroxyprogesterone acetate-DMPA (1mg/mouse). The mice were euthanized at 8 and 12 weeks of age and the reproductive tract was removed. H&E stained sections were used to histologically and pathologically characterize the FTs following treatment. In addition, immunohistochemistry and immunofluorescence were used to characterize lesions and the cell death pathway. <h3>Results:</h3> There was an increase in the number of FT epithelial and stromal p53 positive cells from 5 to 12 weeks of age in the vehicle treated mice. Histologically, the FT of the vehicle treated mice developed adenocarcinoma and/or epithelial/smooth muscle hyperplasia at 8 and 12 weeks of age. Compared to the vehicle-treated mice, the FT of the DMPA treated mice were significantly smaller at 8 weeks (p<0.005) and 12 weeks (p<0.0005) of age. In addition, there was normal distribution of ciliated cells, less nuclear pleomorphism and epithelial tufting, and a significantly lower proliferative index (Ki67) (p=0.001) in 8 week DMPA treated mice compared to vehicle. Accumulation of p53 in the FT was significantly reduced in DMPA(p<0.000005) treated mice at 8 weeks compared to vehicle. There was significantly more cleaved caspase-3 in the FT of the DMPA-treated group compared to the vehicle group. <h3>Conclusions:</h3> DMPA treatments significantly reduced the tumor burden and aberrant p53 expression in the FT of mice compared to vehicle treated animals. Our data support the hypothesis that progestins have a cytocidal effect, clearing genetically damaged cells from the fallopian tube potentially via apoptosis. These data provide evidence supporting the hypothesis that progestin may be used for prevention of ovarian cancer.

Effects of chronic sublethal progestogen exposure on development, reproduction, and detoxification system of water flea, Daphnia magna

The presence of sex steroid hormones in aquatic ecosystems is of rapidly growing concern worldwide since they can affect the different non-target species including cladocerans. Although data are available on the effects of estrogens on the well-established ecotoxicological model organism Daphnia magna, the molecular or behavioural alterations induced by environmentally relevant concentrations (from a few ng L−1 to a few hundred ng L−1 in average) of progestogens have not been investigated on this species. In the present study, we exposed neonates of D. magna to relevant equi-concentrations (1, 10, 100, 500 ng L−1) of mixtures of four progestogens (progesterone, drospirenone, gestodene, levonorgestrel) in short-term (6 days) and long-term (21 days) experiments. Significant alterations were observed at the molecular, cellular, and individual levels. During the short-term exposure, all of the mixtures increased the gene expression of glutathione S-transferase (GST) detoxification enzyme, moreover, the activity of GST was also significantly increased at the concentrations of 10, 100, and 500 ng L−1. In long-term exposure, the number of days until production of the first eggs was reduced at the 10 ng L−1 concentration compared to control, furthermore, the maximum egg number per individual increased at the concentrations of 1 and 10 ng L−1. Based on the authors' best knowledge, this is the first study to investigate the effects of progestogens in mixtures and at environmentally relevant concentrations on D. magna. Our findings contribute to the understanding of the possible physiological effects of human progestogens. Future research should be aimed at understanding the potential mechanisms (e.g., perception) underlying the changes induced by progestogens.

What is behind the fear of cancer during menopausal hormone therapy in China?

The application of menopausal hormone therapy (MHT) is generally restricted most likely due to limited prescriptions by doctors. Fear of cancer risk may be a critical factor. We investigated the views of Chinese obstetricians and gynecologists on the relationship between hormone therapy and cancer risk. A self-administered web-based nationwide cross-sectional questionnaire. In total, 5243 medical workers responded to the questionnaire (response rate 94.5%); 4995 were certified obstetricians and gynecologists. Most were aged 36-55years (70.9%), had > 10years of working experience (68.5%), and worked at tertiary (34.8%) and secondary hospitals (49.1%); 70% of the clinicians were aware of the endometrial cancer risk caused by estrogen, and 20% considered progestogen to cause the same risk. Regarding breast cancer, while 67.9 and 74.8% of the clinicians viewed natural and synthetic estrogens as risk factors, respectively, only 41.7% identified the carcinogenic effect of progestins as higher than that of progesterone (26.7%). Approximately 75% of the participants believed synthetic estrogens and progestins constituted a risk for ovarian cancer (higher than the percentages for their natural counterparts); 13.0-21.1% of the respondents were worried about choriocarcinoma due to hormone treatment. Finally, 86.8% of obstetricians and gynecologists claimed to have poor knowledge regarding this field. Misconceptions and a lack of knowledge in this regard may result in the fear of cancer and could be the underlying causes of limited MHT prescriptions. We believe that scientific research, continued education, and the media all have roles to play in changing preconceived ideas regarding MHT prescriptions.

Effects of progestogens on experimental atherosclerosis

Effects of progestogens on experimental atherosclerosis

Effect of oral contraceptives on total and bioavailable 25-hydroxyvitamin D

Studies show an increase in circulating levels of 25-hydroxyvitamin D [25(OH)D] in women using combined oral contraceptives (COCs). 25(OH)D is a quantitatively important metabolite and widely used clinical marker of vitamin D status and is regulated by vitamin D binding protein (VDBP). However, studies have not identified the type of formulations used by the women, and there are no data on the effect of progestins on 25(OH)D levels. Our study objective was to compare the effects of two COC formulations [ethinyl estradiol (EE)/norethindrone acetate (NETA) vs. EE/levonorgestrel (LNG)] as well as LNG alone on total and bioavailable (free plus albumin-bound) 25(OH)D levels in serum samples collected at baseline, mid treatment, and end of treatment. Total 25(OH)D and VDBP were measured by immunoassay, and bioavailable 25(OH)D was calculated. The results show that with the EE/NETA formulation, total and bioavailable 25(OH)D and VDBP levels increased non-significantly by 7.4 %, 14.9 %, and 10 %, respectively, from baseline to end of treatment. In contrast, the corresponding changes with EE/LNG showed an increase of 4.4 % in total 25(OH)D but a significant decrease of 18.2 % in bioavailable 25(OH)D and increase of 19.1 % in VDBP. When LNG was administered alone, no significant changes were observed in total and bioavailable 25(OH)D or VDBP levels during the course of treatment. Our findings show considerably different effects on total and bioavailable 25(OH)D levels, as well as VDBP levels, with different oral contraceptive formulations. LNG may have a suppressive effect on VDBP, similar to its well-known androgenic effect on SHBG. Further studies are needed to determine the effect of hormonal contraceptive formulations on vitamin D status and its potential impact on women’s health.

Progesterone's Effects on Cognitive Performance of Male Mice Are Independent of Progestin Receptors but Relate to Increases in GABAA Activity in the Hippocampus and Cortex.

Progestogens' (e.g., progesterone and its neuroactive metabolite, allopregnanolone), cognitive effects and mechanisms among males are not well-understood. We hypothesized if progestogen's effects on cognitive performance are through its metabolite allopregnanolone, and not actions via binding to traditional progestin receptors (PRs), then progesterone administration would enhance performance in tasks mediated by the hippocampus and cortex, coincident with increasing allopregnanolone concentrations, brain derived neurotrophic factor (BDNF) and/or muscimol binding of PR knock out (PRKO) and wild-type PR replete mice. Experiment 1: Progesterone (4 mg/kg, subcutaneously (SC; n = 12/grp), or oil vehicle control, was administered to gonadally-intact adult male mice PRKO mice and their wild-type counterparts and cognitive behaviors in object recognition, T-maze and water maze was examined. Progesterone, compared to vehicle, when administered post-training increased time investigating novel objects by the PRKO and wild-type mice in the object recognition task. In the T-maze task, progesterone administration to wild-type and PRKO mice had significantly greater number of spontaneous alternations compared to their vehicle-administered counterparts. In the water maze task, PRKO mice administered vehicle spent significantly fewer seconds in the quadrant associated with the escape platform on testing compared to all other groups. Experiment 2: Progesterone administered to wild-type and PRKO mice increased plasma progesterone and allopregnanolone levels (n = 5/group). PRKO mice had higher allopregnanolone levels in plasma and hippocampus, but not cortex, when administered progesterone and compared to wild-type mice. Experiment 3: Assessment of PR binding revealed progesterone administered wild-type mice had significantly greater levels of PRs in the hippocampus and cortex, compared to all other groups (n = 5/group). Wild-type mice administered progesterone, but not vehicle, had increased BDNF levels in the hippocampus, but not the cortex, compared to PRKOs. Wild-type as well as PRKO mice administered progesterone experienced significant increases in maximal GABAA agonist, muscimol, binding in hippocampus and cortex, compared to their vehicle-administered counterparts. Thus, adult male mice can be responsive to progesterone for cognitive performance, and such effects may be independent of PRs trophic actions of BDNF levels in the hippocampus and/or increases in GABAA activity in the hippocampus and cortex.

The effects of progestin-only hormone treatment on QT interval in the adolescent female

BackgroundProlongation of the ECG derived QT interval predicts increased risk for sudden life-threatening arrhythmias. Many medicines are known to prolong the QT interval though current data demonstrate that progesterone given to premenopausal females <18 years shortens the QT interval by six msec. This effect may be used to treat individuals with abnormal prolongation of the QT interval. Hormone progestin is used to treat a number of conditions in post-menarche females >18 years old. The effects of this treatment on the corrected QT (QTc) in this population are unknown. ObjectiveTo describe the effect of exogenous progestin on the QTc in adolescent females. MethodsIn post-menarcheal females, <18 years old, using no medications with known ECG effects, we compared QTc in milliseconds (ms) on ECG evaluations in those taking exogenous progestin vs those who are not. Descriptive statistics were used to compare the groups. ResultsThere were 40 controls and 21 treated participants. The age range was 10 – 17 years. There were no differences between the groups with regard to race, height, weight, BMI, or blood pressure. In the controls, the mean QTc was 403 +/-19 milliseconds (ms) vs. 397 +/-15 ms in those treated (p=0.22). Those on progestin therapy had a shorter QTc by the same magnitude difference (six ms) as the hormonal naïve group in the adult literature. ConclusionsWe report no adverse effects of progestin associated with QTc prolongation and a trend suggesting a decreased QTc in a population of post menarcheal-adolescent females.

Progestogen-induced alterations and their ecological relevance in different embryonic and adult behaviours of an invertebrate model species, the great pond snail (Lymnaea stagnalis)

The presence of oral contraceptives (basically applying estrogens and/or progestogens) poses a challenge to animals living in aquatic ecosystems and reflects a rapidly growing concern worldwide. However, there is still a lack in knowledge about the behavioural effects induced by progestogens on the non-target species including molluscs. In the present study, environmental progestogen concentrations were summarised. Knowing this data, we exposed a well-established invertebrate model species, the great pond snail (Lymnaea stagnalis) to relevant equi-concentrations (1, 10, 100, and 500 ng L−1) of mixtures of four progestogens (progesterone, drospirenone, gestodene, levonorgestrel) for 21 days. Significant alterations were observed in the embryonic development time, heart rate, feeding, and gliding activities of the embryos as well as in the feeding and locomotion activity of the adult specimens. All of the mixtures accelerated the embryonic development time and the gliding activity. Furthermore, the 10, 100, and 500 ng L−1 mixtures increased the heart rate and feeding activity of the embryos. The 10, 100, and 500 ng L−1 mixtures affected the feeding activity as well as the 1, 10, and 100 ng L−1 mixtures influenced the locomotion of the adult specimens. The differences of these adult behaviours showed a biphasic response to the progestogen exposure; however, they changed approximately in the opposite way. In case of feeding activity, this dose-response phenomenon can be identified as a hormesis response. Based on the authors’ best knowledge, this is the first study to investigate the non-reproductive effects of progestogens occurring also in the environment on molluscan species. Our findings contribute to the global understanding of the effects of human progestogens, as these potential disruptors can influence the behavioural activities of non-target aquatic species. Future research should aim to understand the potential mechanisms (e.g., receptors, signal pathways) of progestogens induced behavioural alterations.

What are the effects of adjuvant progestogens for women with endometrial cancer?

What are the effects of adjuvant progestogens for women with endometrial cancer?

Novel Medicine for Endometriosis and Its Therapeutic Effect in a Mouse Model.

Current therapeutic medicines for endometriosis cannot be administered during assisted reproductive technology (ART) because they have bad effects during pregnancy. In this study, we created an animal model of endometriosis and evaluated the therapeutic effect of progestin (Dienogest), dopamine agonist (Cabergoline), and their combination (Dienogest + Cabergoline). We established a mouse model mimicking human endometriosis. The mice with endometriosis were then treated with a single drug (Dienogest or Cabergoline) or both drugs (Dienogest + Cabergoline) for 14 days. An immunohistological study was then performed to analyze inflammatory lesions in the recipient mice. Real-time polymerase chain reaction (RT-PCR) and Western blotting were also performed to determine the levels of genes and proteins in inflammatory lesions to assess the recovery of endometriosis. Histologic staining showed that all medication groups showed a clear decrease in the inflammatory phenotype in the uterus, peritoneum, and intestine. Gene and protein expression analysis showed a therapeutic effect in all medication groups. In conclusion, Cabergoline had a therapeutic effect similar to that of Dienogest and could be used as an alternative to Dienogest during ART for patients with infertility; compared to the individual drugs, the combination treatment has a synergistic effect on endometriosis.

Uterine Fibroids and Progestogen Treatment: Lack of Evidence of Its Efficacy: A Review.

Background: The objective of this review is to determine the evidence or, conversely, the absence of evidence regarding the effectiveness of progestogens in treating premenopausal women with uterine fibroids. In particular, the goal is to address recurring questions as to whether they are effective or not for managing symptoms commonly attributed to fibroids. Methods: A review of the most relevant papers (n = 63) on the efficacy of progesterone and progestogens as medical therapy for uterine fibroids. Results: Having reviewed the most significant papers on the relationship between uterine fibroids and progesterone/progestogens, it is clear that there is biochemical, histological and clinical evidence that progesterone and progestogens play a critical role in the pathogenesis of myomas. Conclusion: Since progesterone is already implicated in the pathogenesis of this entity, using progestogens to manage fibroids is like constantly adding fuel to the fire, rendering this treatment ineffective.

Progestogens or progestogen-releasing intrauterine systems for uterine fibroids (other than preoperative medical therapy).

Uterine fibroids can cause heavy menstrual bleeding. Medical treatments are considered to preserve fertility. It is unclear whether progestogens or progestogen-releasing intrauterine systems can reduce fibroid-related symptoms. This is the first update of a Cochrane Review published in 2013. To determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and PsycINFO databases to July 2020. We also searched trials registers for ongoing and registered trials, and checked references of relevant trials. All identified published or unpublished randomised controlled trials (RCTs) assessing the effect of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. Two authors independently extracted data, assessed risk of bias, and assessed the quality of the evidence using the GRADE approach. This updated review included four studies with 221 women with uterine fibroids. The evidence was very low quality, downgraded for serious risk of bias, due to poor reporting of study methods, and serious imprecision. Levonorgestrel-releasing intrauterine device (LNG-IUS) versus hysterectomy There was no information on the outcomes of interest, including adverse events. LNG-IUS versus low dose combined oral contraceptive (COC) At 12 months, we are uncertain whether LNG-IUS reduced the percentage of abnormal uterine bleeding, measured with the alkaline hematin test (mean difference (MD) 77.50%, 95% confidence interval (CI) 70.44 to 84.56; 1 RCT, 44 women; very low-quality evidence), or the pictorial blood assessment chart (PBAC; MD 34.50%, 95% CI 11.59 to 57.41; 1 RCT, 44 women; very low-quality evidence); increased haemoglobin levels (MD 1.50 g/dL, 95% CI 0.85 to 2.15; 1 RCT, 44 women; very low-quality evidence), or reduced fibroid size more than COC (MD 1.90%, 95% CI -12.24 to 16.04; 1 RCT, 44 women; very low-quality evidence). The study did not measure adverse events. LNG-IUS versus oral progestogen (norethisterone acetate (NETA)) Compared to NETA, we are uncertain whether LNG-IUS reduced abnormal uterine bleeding more from baseline to six months (visual bleeding score; MD 23.75 points, 95% CI 1.26 to 46.24; 1 RCT, 45 women; very low-quality evidence); increased the percentage of change in haemoglobin from baseline to three months (MD 4.53%, 95% CI 1.46 to 7.60; 1 RCT, 48 women; very low-quality evidence), or from baseline to six months (MD 10.14%, 95% CI 5.57 to 14.71; 1 RCT, 45 women; very low-quality evidence). The study did not measure fibroid size. Spotting (adverse event) was more likely to be reported by women with the LNG-IUS (64.3%) than by those taking NETA (30%; 1 RCT, 45 women; very low-quality evidence). Oral progestogen (dienogest, desogestrel) versus goserelin acetate Compared to goserelin acetate, we are uncertain whether abnormal uterine bleeding was reduced at 12 weeks with dienogest (PBAC; MD 216.00 points, 95% CI 149.35 to 282.65; 1 RCT, 14 women; very low-quality evidence) or desogestrel (PBAC; MD 78.00 points, 95% CI 28.94 to 127.06; 1 RCT, 16 women; very low-quality evidence). Vasomotor symptoms (adverse events, e.g. hot flashes) are only associated with goserelin acetate (55%), not with dienogest (1 RCT, 14 women; very low-quality evidence) or with desogestrel (1 RCT, 16 women; very low-quality evidence). The study did not report fibroid size. Because of very low-quality evidence, we are uncertain whether the LNG-IUS reduces abnormal uterine bleeding or increases haemoglobin levels in premenopausal women with uterine fibroids, compared to COC or norethisterone acetate. There was insufficient evidence to determine whether the LNG-IUS reduces the size of uterine fibroids compared to COC. We are uncertain whether oral progestogens reduce abnormal uterine bleeding as effectively as goserelin acetate, but women reported fewer adverse events, such as hot flashes.

Chemopreventive effect of progestin and vitamin D in the mogp-TAG ovarian cancer mouse model

Objective: Growing evidence suggests the fallopian tube epithelium harbors the precursor for high-grade serous ovarian cancer, creating opportunities for targeting the fallopian tube for effective chemoprevention. Animal and human evidence has shown that progestins confer potent cancer preventive effects in the gynecologic tract by activating molecular pathways that clear genetically damaged cells. in addition, it has been shown in vitro that the potency of progestins can be enhanced with vitamin D.

Progestins for pituitary suppression during ovarian stimulation for ART: a comprehensive and systematic review including meta-analyses.

Progestins are capable of suppressing endogenous LH secretion from the pituitary. Progestins can be used orally and are less expensive than GnRH analogues. However, early endometrial exposure to progestin precludes a fresh embryo transfer (ET), but the advent of vitrification and increasing number of oocyte cryopreservation cycles allow more opportunities for using progestins for pituitary suppression. This review summarizes: the mechanism of pituitary suppression by progestins; the effectiveness of progestins when compared with GnRH analogues and with each other; the effect of progestins on oocyte and embryo developmental potential and euploidy status; and the cost-effectiveness aspects of progestin primed stimulation. Future research priorities are also identified. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, the Web of Science and Scopus were screened with a combination of keywords related to ART, progesterone, GnRH analogue and ovarian stimulation, in various combinations. The search period was from the date of inception of each database until 1 April 2020. Only full text papers published in English were included. Overall, the duration of stimulation, gonadotrophin consumption and oocyte yield were similar with progestins and GnRH analogues. However, sensitivity analyses suggested that progestins were associated with significantly lower gonadotrophin consumption than the long GnRH agonist protocol (mean difference (MD) = -648, 95% CI = -746 to -550 IU) and significantly higher gonadotrophin consumption than the short GnRH agonist protocol (MD = 433, 95% CI = 311 to 555 IU). Overall, live birth, ongoing and clinical pregnancy rates per ET were similar with progestins and GnRH analogues. However, when progestins were compared with GnRH agonists, sensitivity analyses including women with polycystic ovary syndrome (risk ratio (RR) = 1.27, 95% CI = 1.06 to 1.53) and short GnRH agonist protocols (RR = 1.14, 95% CI = 1.02 to 1.28) showed significantly higher clinical pregnancy rates with progestins. However, the quality of evidence is low. Studies comparing medroxyprogesterone acetate, dydrogesterone and micronized progesterone suggested similar ovarian response and pregnancy outcomes. The euploidy status of embryos from progestin primed cycles was similar to that of embryos from conventional stimulation cycles. Available information is reassuring regarding obstetric and neonatal outcomes with the use of progestins. Despite the lower cost of progestins than GnRH analogues, the mandatory cryopreservation of all embryos followed by a deferred transfer may increase cost per live birth with progestins as compared to an ART cycle culminating in a fresh ET. Progestins can present an effective option for women who do not contemplate a fresh ET, e.g. fertility preservation, anticipated hyper responders, preimplantation genetic testing, oocyte donors, double stimulation cycles.

Adenomyosis: clinical aspects, impact on fertility and pregnancy outcome

Aim. To investigate the modern condition of the problem of adenomyosis and its impact on womens reproductive function.&#x0D; Material and methods. The article presents a systematic literature review on the results of research search in electronic databases MEDLINE, PubMed, EMBASE, Cochrane Library and Elibrary.&#x0D; Results. Adenomyosis is a common but insufficiently studied disease. Modern imaging methods, such as transvaginal ultrasound and MRI, make it possible to diagnose adenomyosis at the early stages of the disease and perform the organ-preserving surgery. A medical treatment of adenomyosis requires to develop a lifelong management plan, the choice depends on the womans age, reproductive status and clinical symptoms. Currently, there is evidence of a negative impact of adenomyosis on fertility and pregnancy outcomes. Dienogest, a 19-norsteroid derivative, is a progestin with high selectivity to progesterone receptors, it exerts a hypogonadotropic effect and an antiproliferative effect on the endometrium. A mild regime of supression of ovarian function provides adequate conditions for blood supply to the uterus before planning a pregnancy. The immunomodulating effect of progestin may be useful for implantation and fetal protection to pregnancies occurring after treatment. Dienogest treatment increases the effectiveness of IVF cycles for adenomyosis of varying severity.&#x0D; Conclusion. The review summarizes the aspects of prevalence, comorbidity, risk factors, classification, mechanism of pathogenesis, clinical manifestations, diagnosis, treatment of adenomyosis, impact on fertility and pregnancy outcomes.

The effects of norethindrone on the ontogeny of gene expression along the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes in zebrafish (Danio rerio)

Little is known about the molecular effects of progestins on the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes in fish prior to sexual differentiation. In this study, the effects of norethindrone (NET) on the ontogeny of HPG- and HPA-related genes in zebrafish embryo/early larvae prior to sexual differentiation were evaluated. Embryo/larvae were exposed to different concentrations (5, 50, 500 ng/L) of NET for 6 days. The levels of the transcripts of the genes closely related to the HPG and HPA axes were determined daily during 3 stages (embryo, embryo/larvae transition, and early larvae). The results showed that most genes were up-regulated and the ontogeny of genes in the HPA axis was earlier than that of HPG axis, especially for the upstream genes of both the HPG (gnrh2, gnrh3, fshb, lhb) and the HPA (crh, pomc, star) axes. In contrast, the transcriptional expressions of genes of the cortisol/stress pathway (cyp11b, mr) were inhibited and those of the progesterone pathway were not affected. More importantly, NET exposure induced the expressions of the genes (esr1, vtg1, hsd17b3, hsd11b2, ar) that are closely related to the steroid hormone pathways in the embryos/larvae stages, implying a precocious effects of NET in zebrafish. This study demonstrates that NET alters the expression of HPA- and HPG-axes related genes in zebrafish at early stages, pointing to the need for the same type of analysis during the zebrafish gonadal differentiation window.