Developmental 17-OHPC exposure disrupts behavior regulated by the mesocorticolimbic dopaminergic system in rats.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals with the intention of reducing preterm birth. Although there is evidence that 17-OHPC is likely transferred from mother to fetus, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. Neonatal 17-OHPC exposure disrupts the development of the mesocorticolimbic dopaminergic pathway and associated behaviors in rats. 17-OHPC exposure altered dopaminergic innervation of prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents and altered performance in measures of decision-making, set-shifting, and reversal-learning tasks. The present study tested the effects of developmental 17-OHPC exposure on numerous cognitive behaviors mediated by the mesocorticolimbic dopaminergic system, such as decision-making in a delay discounting task, latent inhibition following conditioned taste aversion (CTA), and spatial memory in the Morris Water Maze (MWM). The present work also aimed to further investigate response omissions in rats exposed to 17-OHPC during development and the potential role of dopamine D2 receptor in altering omissions in a delay discounting task. 17-OHPC exposure rendered rats less sensitive to an Eticlopride-induced increase in omissions in a delay discounting task when compared to controls. Quinpirole flattened the discount curve in both groups but did not significantly affect omissions in 17-OHPC-exposed or control rats. Following CTA, sucrose-pre-exposed 17-OHPC-exposed rats demonstrated decreased latent inhibition when compared to controls. In Morris Water Maze testing, 17-OHPC-exposed rats did not differ from controls after the first day of testing or during probe testing. These results suggest that exposure to 17-OHPC altered aspects of decision-making and latent inhibition in adult male rats, without affecting performance in a measure of spatial learning and memory. Further, the insensitivity of 17-OHPC-exposed males to an Eticlopride-induced increase in omissions suggests a dysfunction in the D2 receptor following exposure to this clinically used synthetic progestin.

Potential effect of immediate postpartum use of injectable contraception on lactogenesis.

OBJECTIVES: We evaluated the effect of immediate postpartum use of depot medroxyprogesterone acetate (DMPA) on the timing of lactogenesis stage II (LS-II). STUDY DESIGN: The initial design randomly assigned adults who delivered a full-term infant in 2019-2021 to receive within 48 hours of delivery: 1) DMPA, 2) placebo injection, or 3) no injection. Due to low enrollment, we changed in 2021-2023 to a non-randomized design using matching at recruitment for obesity and delivery method and propensity score weighting for analysis. We combined data from both designs to compare immediate postpartum DMPA use (N=55) versus control (placebo or no injection) group (N=95). We defined noninferiority a priori as being met if the upper bound of a two-sided 95% confidence interval (CI) for mean difference in time to LS-II between groups was <6 hours. RESULTS: The unweighted mean time to LS-II was 57.8 hours in the DMPA group (SD, 29.4) and 64.1 hours in the control group (SD, 36.1). Using propensity score weighting to make the groups comparable with respect to age, race, delivery method, and previous live births, the mean time to LS-II was 5.5 hours shorter (95% CI, -16.4, 5.5) for women in the DMPA relative to control group. CONCLUSIONS: We found no evidence that DMPA use inhibits the onset of LS-II. Findings support immediate postpartum DMPA initiation among those intending to engage in human milk feeding. IMPLICATIONS: A controlled trial (N=150) did not detect any difference in time to lactogenesis stage II ("milk let-down") between injectable contraception use within the first 48 hours postpartum and those without this exposure.

Impact of Etonogestrel-releasing contraceptive implant use in cisgender women with Sickle cell disease.

BACKGROUND: Sickle cell disease is a hereditary hemolytic anemia that exposes women to increased health risks especially in pregnancy, with serious implications for the woman and fetus. Acute pain episodes can occur multiple times per month and result in reduction of quality of life and disruption of her life. OBJECTIVE: To assess the clinical, including pain and metabolic parameters of women with sickle cell disease using etonogestrel-releasing contraceptive implants. METHODS: Women with sickle cell disease, aged 18-40 years, with reports of pain crises in the preceding 3 months were included and followed up for 12 months. Blood samples were collected to evaluate the blood count, reticulocytes, liver profile (alkaline phosphatase, gamma-glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin and its fractions), lipid profile, and lactate dehydrogenase levels before and 6 and 12 months after implant insertion. The following clinical variables were analyzed every 3 months: bleeding pattern, blood pressure, weight, body mass index, pain intensity (assessed using a visual analogic scale (VAS) from 0 to 10), and frequency of pain crises. RESULTS: Twenty-three women completed the study. There were no differences in laboratory variables between baseline and 6 and 12 months after implant insertion. Similarly, clinical variables did not differ, except for pain intensity (VAS pre-insertion = 8 vs. VAS 12 months post insertion = 4; p = 0.005) and frequency of pain crises (pre-insertion = 6 vs. 12 days/month post insertion = 0; p = 0.000). CONCLUSIONS: Etonogestrel-releasing contraceptive implants were associated with a reduction in the intensity and frequency of pain crises in women with sickle cell disease. Moreover, it was safety among these population due to no changes in laboratory parameters during the first 12 months of use.

17α-Ethynylestradiol and Levonorgestrel Exposure of Rainbow Trout RTL-W1 Cells at 18 °C and 21 °C Mainly Reveals Thermal Tolerance, Absence of Estrogenic Effects, and Progestin-Induced Upregulation of Detoxification Genes.

Fish are exposed to increased water temperatures and aquatic pollutants, including endocrine-disrupting compounds (EDCs). Although each stressor can disturb fish liver metabolism independently, combined effects may exist. To unveil the molecular mechanisms behind the effects of EDCs and temperature, fish liver cell lines are potential models needing better characterisation. Accordingly, we exposed the rainbow trout RTL-W1 cells (72 h), at 18 °C and 21 °C, to ethynylestradiol (EE2), levonorgestrel (LNG), and a mixture of both hormones (MIX) at 10 µM. The gene expression of a selection of targets related to detoxification (CYP1A, CYP3A27, GST, UGT, CAT, and MRP2), estrogen exposure (ERα, VtgA), lipid metabolism (FAS, FABP1, FATP1), and temperature stress (HSP70b) was analysed by RT-qPCR. GST expression was higher after LNG exposure at 21 °C than at 18 °C. LNG further enhanced the expression of CAT, while both LNG and MIX increased the expressions of CYP3A27 and MRP2. In contrast, FAS expression only increased in MIX, compared to the control. ERα, VtgA, UGT, CYP1A, HSP70b, FABP1, and FATP1 expressions were not influenced by the temperature or the tested EDCs. The RTL-W1 model was unresponsive to EE2 alone, sensitive to LNG (in detoxification pathway genes), and mainly insensitive to the temperature range but had the potential to unveil specific interactions.

GnRH-a-based fertility-sparing treatment of atypical endometrial hyperplasia (AEH) and early endometrial carcinoma (EC) patients: a multicenter, open-label, randomized designed clinical trial protocol.

BACKGROUND: Around 4% of women receive an endometrial cancer diagnosis before turning 40, mainly those without prior childbirth experience and a strong desire to preserve their ability to conceive. Consequently, for young patients diagnosed with atypical endometrial hyperplasia (AEH) or early endometrial carcinoma (EC), a fertility-preserving approach employing high-dose oral progesterone has been adopted. However, previous research has shown a notable relapse rate. Furthermore, the extended use of substantial oral progesterone doses may hinder ovarian function and raise the risk of weight gain, liver issues, blood clotting, and breast cancer. We previously assessed the clinical effectiveness and pregnancy outcomes of gonadotropin-releasing hormone agonist (GnRH-a) based re-treatment for women with EC and AEH who did not respond to oral progestin therapy but achieved favorable treatment results and reproductive outcomes. METHODS: This study will be an open-label, two-armed, randomized, investigator-initiated multicenter trial evaluating the combination of GnRH-a with the levonorgestrel-releasing intrauterine system or the combination of GnRH-a with an aromatase inhibitor (comprising a subcutaneous GnRH-a injection every 4 weeks and daily oral letrozole 2.5 mg). A total of 226 participants will be randomly allocated to one of the two treatment groups in a 1:1 ratio. The primary objective is to determine the effectiveness of GnRH-a-based re-treatment in achieving a complete response (CR) at 24 weeks for patients with AEH or EC. Secondary objectives include assessing the pregnancy rate 12 weeks after treatment, as well as post-treatment pregnancy outcomes and the rate of recurrence. ETHICS AND DISSEMINATION: The protocol received approval from the Institutional Review Board of Peking Union Medical College Hospital and from boards at five other institutions. The trial will adhere to the principles outlined in the World Medical Association's Declaration of Helsinki and follow Good Clinical Practice standards. The trial results will be disseminated through publication in a peer-reviewed journal. CONCLUSIONS: Prospective evidence supporting conservative treatment for EC and AEH is limited. There is a need for new approaches that can achieve higher CR rates with fewer side effects. This trial will assess the effectiveness of GnRH-a-based fertility-sparing treatment in obese women and recurrent patients, offering a promising alternative for patients with EC and AEH. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry ChiCTR2200067099. Registered on December 27, 2022.

Systematic review and meta-analysis of the effects of progestins on depression in post-menopausal women: An evaluation of randomized clinical studies that used validated questionnaires.

OBJECTIVE: Hormone therapy (HT) can relieve symptoms of menopause and treat chronic diseases. Its effectiveness in treating psychological symptoms is still debated. Several progestins can be used in HT, but their effects on mood, in particular depressive symptoms, is still unclear. This systematic review evaluates the evidence from randomized clinical trials with postmenopausal women on the effect of adjunctive progestins on symptoms of depression assessed by validated questionnaires. The primary aim was to evaluate scores on the Center for Epidemiologic Studies Depression Scale (CESD). The secondary aim was to assess scores on the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HAMD), and the Zung Self-Rating Depression Scale (SDS). METHODS: A systematic review and meta-analysis were conducted to identify the most reliable evidence of the effects of progestin on depression to inform decision-making. A PICO- and PRISMA-based framework was established to formulate explicit and reasoned recommendations. The pre-/post-treatment effect was evaluated using standardized mean change (SMC). RESULTS: We selected and analyzed 16 randomized clinical trials qualitatively and 12 studies quantitatively out of 9320 items identified. Most of the studies used medroxyprogesterone acetate as progestin. The results indicate that depressive symptoms do not increase with the addition of a progestin to estrogen HT. Depressive symptoms improved over time in the progestins-estrogen HT group, independent of progestin type (SMC CES-D -0.08 CI.95-0.10/-0.06, BDI -0.19 CI.95-0.32/-0.06, HAM-D -1.13 CI.95-1.47/-0.78, and SDS -0.11 CI.95-0.82/0.60). Yet similar effects were observed with estrogens alone and did not significantly differ from control groups on placebo. In one study, the addition of fluoxetine greatly increased the reduction of depressive symptoms observed with estrogen-progestin HT. CONCLUSIONS: In summary, in randomized clinical trials using validated questionnaires adjunctive progestin with estrogens did not increase depressive symptoms of postmenopausal women. Overall, depressive symptoms decreased with estrogen-progestin HT but also with estrogen alone. The decrease was not so pronounced to differ from controls on placebo. HT does not hamper the clinical efficacy of fluoxetine. The scarcity of randomized studies makes it difficult to determine the exact effect on depressive symptoms of different types of progestins. Project protocol registered in PROSPERO, registration number CRD42023454099.

Implications of Developmental 17-OHPC Exposure on the Mesocorticolimbic Serotonergic and Dopaminergic Pathways and Adolescent Mood-Related Behavior in Rats.

The synthetic progestin, 17-α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for recurrent preterm birth during a critical period of fetal mesocorticolimbic serotonergic and dopaminergic pathway development. These pathways play an important role in regulating cognitive behaviors later in life. Despite this, there has been very little research regarding the potential long-term effects of 17-OHPC on the behavioral and neural development of exposed children. In rodents, developmental exposure to 17-OHPC disrupts serotonergic and dopaminergic innervation of the medial prefrontal cortex and impairs decision-making in complex cognitive tasks in adulthood. The present study tested the hypothesis that developmental exposure to 17-OHPC similarly disrupts the development of serotonergic and dopaminergic pathways within limbic targets and subsequent mood-related behaviors. Developmental 17-OHPC exposure significantly increased the density of serotonin transporter-IR fibers in CA1, CA2/3, and the suprapyramidal blade of dentate gyrus in hippocampus and significantly reduced the density of TH-IR fibers within the nucleus accumbens shell in males but had no effect in females during adolescence. Irregular microglia activational phenotype and number were also observed in the hippocampus of 17-OHPC-exposed males. Developmental 17-OHPC reduced the latency to immobility in males in the forced swim test but did not affect sucrose consumption in a sucrose preference test. These findings suggest that 17-OHPC exerts sex-specific effects on the development of mesocorticolimbic pathways and mood-related behavior in adolescence and highlight the need to investigate effects in adolescent children.

Role of sex steroids in colorectal cancer: pathomechanisms and medical applications.

Given that the colon represents the most extensive hormone-responsive tissue in the human body, it prompts a compelling inquiry into whether the progression of its cancer is intimately linked to hormonal dynamics. Consequently, the interplay between sex steroids - a pivotal constituent of hormones - and colorectal cancer has increasingly captivated scientific interest. Upon a comprehensive review of pertinent literature both domestically and internationally, this study delineates the present landscape of three pivotal steroids - estrogen, progestin, and androgen - in the context of colorectal cancer. More specifically, this investigation probes into the potential utility of these steroids in providing therapeutic interventions, diagnostic insights, and prognostic indicators. Furthermore, this study also delves into the mechanistic pathways through which sex steroid interventions exert influence on colorectal cancer. It was discovered that the trio of sex steroid hormones partakes in an array of biological processes, thereby influencing the onset and progression of colorectal cancer. In conclusion, this study posits that a profound interconnection exists between colorectal cancer and sex steroids, suggesting that elucidating the targets of their action mechanisms could unveil novel avenues for the diagnosis and prevention of colorectal cancer.

Antitumor progestins activity: Cytostatic effect and immune response.

Progestins are used to treat some hormone-sensitive tumors. This review discusses the mechanisms of progestins' effects on tumor cells, the differences in the effects of progesterone and its analogs on different tumor types, and the influence of progestins on the antitumor immune response. Progestins cause a cytostatic effect, but at the same time they can suppress the antitumor immune response, and this can promote the proliferation and metastasis of tumor cells. Such progestins as dienogest, megestrol acetate and levonorgestrel increase the activity of NK-cells, which play a major role in the body's fight against tumor cells. The use of existing progestins and the development of new drugs with gestagenic activity may hold promise in oncotherapy.

Use of serum evaluation of contraceptive and ovarian hormones to assess reduced risk of pregnancy among women presenting for emergency contraception in a multicenter clinical trial.

OBJECTIVES: To evaluate ovulation risk among women enrolling in an emergency contraception (EC) study by measuring contraceptive steroids and ovarian hormones. STUDY DESIGN: We used standard chemiluminescent assays to evaluate endogenous hormones (estradiol, progesterone, follicle stimulating hormone, luteinizing hormone) and liquid chromatography-tandem triple quadrupole mass spectrometry to simultaneously analyze concentrations of ethinylestradiol, dienogest, norelgestromin (NGMN), norethindrone (NET), gestodene, levonorgestrel (LNG), etonogestrel (ENG), segesterone acetate, medroxyprogesterone acetate (MPA), and drospirenone in serum samples obtained at the time of enrollment in a recent study comparing oral ulipristal acetate and LNG EC in women with weight ≥80 kg reporting no recent use of hormonal contraception. RESULTS: We enrolled 532 and obtained a valid baseline blood sample from 520 women. Of these, 117 (22.5%) had detectable concentrations of progestin (MPA [n = 58, 11.2%], LNG [50, 9.6%], ENG [11, 2.1%], NET [5, 0.96%], NGMN [3, 0.06%], or drospirenone [1, 0.02%]). LNG was co-detected in all three participants with samples containing NGMN. Multiple progestins were detected in eight other women: ENG/MPA (1), ENG/LNG (2), and MPA/LNG (5). Samples from 55 (10.6%) had concentrations of one or more progestin considered above the minimum level for contraceptive (MPA ≥ 0.1 ng/mL, n = 19; NGMN/LNG ≥ 0.2 ng/mL, n = 31; ENG ≥ 0.09 ng/mL, n = 8; NET ≥ 0.35 ng/mL, n = 4). We detected concentrations of serum progesterone ≥ 3 ng/mL, indicative of luteal phase (postovulation) status, in an additional 194 (37.3%) samples. CONCLUSIONS: More than one-third of enrolled in our clinical trial of oral EC had evidence of prior ovulation at the time of enrollment. Additionally, about 23% had evidence of recent use of hormonal contraception. These results would have decreased the expected risk of pregnancy in the study. IMPLICATIONS: Many participants in a recent clinical trial of oral emergency contraception did not appear to be at risk for pregnancy or would not have benefited from intervention due to cycle timing. Investigators should consider the effects of these findings on expected pregnancy rates when determining sample size in future EC clinical trials, particularly when using noninferiority designs or historical controls.

Developmental exposure to 17-α-hydroxyprogesterone caproate disrupts decision-making in adult female rats: A potential role for a dopaminergic mechanism.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for preterm birth and is likely transferred from mother to fetus. Yet, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. In rats, neonatal 17-OHPC exposure altered dopaminergic fiber distribution and density in the prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents, respectively. Additionally, neonatal 17-OHPC exposure in male rats increased response omissions in a delay discounting task of impulsive decision-making. Because developmental 17-OHPC exposure has differential effects in males and females, investigating the effects of 17-OHPC on impulsive decision-making in female rats is necessary. The present study tested the effects of developmental 17-OHPC exposure (P1-P14) in a delay discounting task in which female rats chose between a small immediate reward and a larger delayed (0, 15 30, or 45 s) reward. 17-OHPC-exposed females made more omissions than controls. There was no effect of 17-OHPC on large reward preference nor on response time, and omissions were similar during both free- and forced-choice trials. The present study also aimed to investigate the neural mechanisms underlying omissions in 17-OHPC-exposed female rats. The dopamine transporter inhibitor, methylphenidate (MPH), was administered prior to delay discounting testing. MPH treatment did not reduce omissions in 17-OHPC-exposed females. If anything, MPH increased omissions in control females nearly fourfold during the longest delays. These results suggest that developmental 17-OHPC exposure increased omissions without affecting impulsivity or slowing decision-making. Furthermore, omissions may be regulated, at least in part, by dopaminergic mechanisms.

Metabolism of progestogens used for contraception and menopausal hormone therapy.

A variety of progestogens are widely used by women for contraception and menopausal hormone therapy. The progestogens undergo extensive metabolism by oral and parenteral routes of administration to form many metabolites. Although a small number of metabolites have been shown to be biologically active, most have not been tested for biologic activity. The present review shows that we know most about progesterone metabolism, followed by the metabolism of levonorgestrel and norethindrone. Very few studies have been carried out on metabolism of most of the progestogens. The clinical significance of this deficiency is that those progestogen metabolites that bind to the progesterone receptors may also bind to other steroid receptors and be responsible for some of the well-documented side effects of administered progestogens. We also discuss how obesity and genetic polymorphisms alter progestogen metabolism, and how development of oral progestogen formulations that are targeted to the colon, where the concentration of steroid-metabolizing enzymes is much lower than in the proximal gut, may have a beneficial effect on progestogen metabolism.

Occurrence and spatiotemporal distribution of natural and synthetic steroid hormones in soil, water, and sediment systems in suburban agricultural area of Guangzhou City, China.

Steroid hormones are highly potent compounds that can disrupt the endocrine systems of aquatic organisms. This study explored the spatiotemporal distribution of 49 steroid hormones in agricultural soils, ditch water, and sediment from suburban areas of Guangzhou City, China. The average concentrations of Σsteroid hormones in the water, soils, and sediment were 97.7 ng/L, 4460 ng/kg, and 9140 ng/kg, respectively. Elevated hormone concentrations were notable in water during the flood season compared to the dry season, whereas an inverse trend was observed in soils and sediment. These observations were attributed to illegal wastewater discharge during the flood season, and sediment partitioning of hormones and manure fertilization during the dry season. Correlation analysis further showed that population, precipitation, and number of slaughtered animals significantly influenced the spatial distribution of steroid hormones across various districts. Moreover, there was substantial mass transfer among the three media, with steroid hormones predominantly distributed in the sediment (60.8 %) and soils (34.4 %). Risk quotients, calculated as the measured concentration and predicted no-effect concentration, exceeded 1 at certain sites for some hormones, indicating high risks. This study reveals that the risk assessment of steroid hormones requires consideration of their spatiotemporal variability and inter-media mass transfer dynamics in agroecosystems.

Is There a Special Role for Ovarian Hormones in the Pathogenesis of Lobular Carcinoma?

Lobular carcinoma represent the most common special histological subtype of breast cancer, with the majority classed as hormone receptor positive. Rates of invasive lobular carcinoma in postmenopausal women have been seen to increase globally, while other hormone receptor-positive breast cancers proportionally have not followed the same trend. This has been linked to exposure to exogenous ovarian hormones such as hormone replacement therapy. Reproductive factors resulting in increased lifetime exposure to endogenous ovarian hormones have also been linked to an increased risk of lobular breast cancer, and taken together, these data make a case for the role of ovarian hormones in the genesis and progression of the disease. In this review, we summarize current understanding of the epidemiological associations between ovarian hormones and lobular breast cancer and highlight mechanistic links that may underpin the etiology and biology.

Suppression of progesterone by influenza A virus mediates adverse maternal and fetal outcomes in mice.

Influenza A virus infection during pregnancy can cause adverse maternal and fetal outcomes but the mechanism responsible remains elusive. Infection of outbred mice with 2009 H1N1 at embryonic day (E) 10 resulted in significant maternal morbidity, placental tissue damage and inflammation, fetal growth restriction, and developmental delays that lasted through weaning. Restriction of pulmonary virus replication was not inhibited during pregnancy, but infected dams had suppressed circulating and placental progesterone (P4) concentrations that were caused by H1N1-induced upregulation of pulmonary cyclooxygenase (COX)-1-, but not COX-2-, dependent synthesis and secretion of prostaglandin (PG) F2α. Treatment with 17-α-hydroxyprogesterone caproate (17-OHPC), a synthetic progestin that is safe to use in pregnancy, ameliorated the adverse maternal and fetal outcomes from H1N1 infection and prevented placental cell death and inflammation. These findings highlight the therapeutic potential of progestin treatments for influenza during pregnancy.IMPORTANCEPregnant individuals are at risk of severe outcomes from both seasonal and pandemic influenza A viruses. Influenza infection during pregnancy is associated with adverse fetal outcomes at birth and adverse consequences for offspring into adulthood. When outbred dams, with semi-allogenic fetuses, were infected with 2009 H1N1, in addition to pulmonary virus replication, lung damage, and inflammation, the placenta showed evidence of transient cell death and inflammation that was mediated by increased activity along the arachidonic acid pathway leading to suppression of circulating progesterone. Placental damage and suppressed progesterone were associated with detrimental effects on perinatal growth and developmental delays in offspring. Treatment of H1N1-infected pregnant mice with 17-OHPC, a synthetic progestin treatment that is safe to use in pregnancy, prevented placental damage and inflammation and adverse fetal outcomes. This novel therapeutic option for the treatment of influenza during pregnancy should be explored clinically.

Progestins as a Contributing Factor to Hepatocellular Adenoma: A Case Series and Literature Review.

STUDY OBJECTIVE: To explore the role of progestins as potential contributing factors for the development of hepatocellular adenoma (HA) METHODS: We describe 3 cases of adolescents and young adults who developed HA while on norethindrone (NET), as well as their management. In addition, we provide a comprehensive literature review on the association between progestins and HA. RESULTS: Since 1983, 16 cases of HA in patients on progestins have been reported. Ten patients were on NET and 5 on a prodrug of NET (4 on norethindrone acetate [NETA] and 1 on lynestrenol). One individual had a norgestrel implant. Eight subsequently ceased all hormones: 4 experienced a size reduction, and 3 had complete resolution of their HA. Among our patients, 1 ceased NET and instead had a levonorgestrel intrauterine device inserted, and another swapped from NET to oral medroxyprogesterone acetate. Both experienced complete resolution of their HA. The third ceased NET and underwent a hysterectomy, with size reduction of her HA. CONCLUSION: These cases and the literature review suggest an association between progestin exposure, in particular NET and its prodrugs, and the development of HA. The pathophysiology is unknown but may include peripheral conversion of NET and NETA to ethinyl estradiol or a specific action of 19-nortestosterone derivatives on hepatocytes, especially those with higher systemic doses compared with the levonorgestrel intrauterine device. There are no case reports relating to other forms of progestins, such as 17-hydroxyprogesterone, which may be important when considering alternative therapeutic options in females requiring effective menstrual management who have comorbidities.

Progestins and breast cancer hallmarks: The role of the ERK1/2 and JNK pathways in estrogen receptor positive breast cancer cells.

Progestins used in hormonal contraceptives and menopausal hormone therapy (MHT) have been linked to increased breast cancer risk. Whether the association holds for all progestins is unclear and the underlying mechanisms remain poorly understood. We directly compared the effects of four progestins (medroxyprogesterone acetate (MPA), norethisterone acetate (NET-A), levonorgestrel (LNG) and drospirenone (DRSP)) to each other and the natural progestogen progesterone (P4) on selected cancer hallmarks. To provide mechanistic insight into these effects, we assessed the role of the progesterone receptor (PR), and the extracellular signal-related kinase (ERK1/2) and c-Jun N terminal (JNK) signaling pathways. We showed that the increased proliferation of the luminal T47D breast cancer cell line by P4 and all progestins, albeit to different extents, was inhibited by PR knockdown and inhibition of both the ERK1/2 and JNK pathways. While knockdown of the PR also blocked the upregulation of MKI67 and CCND1 mRNA expression by selected progestogens, only a role for the ERK1/2 pathway could be established in these effects. Similarly, only a role for the ERK1/2 pathway could be confirmed for progestogen-induced colony formation, whereas both the ERK1/2 and JNK pathways were required for cell migration in response to the three older progestins implicated in the etiology of breast cancer, MPA, NET-A and LNG. Together our results show that all the progestins elicit their effects on cell proliferation via a mechanism requiring the PR, ERK1/2 and JNK pathways. While the ERK1/2 and JNK pathways are also required for increased cell migration by the older progestins, only a role for the ERK1/2 pathway could be established in their effects on colony formation. Notably, the cytoplasmic PR was not needed for activation of the ERK1/2 pathway by the progestogens. Given that DRSP showed significantly lower proliferation than MPA and NET-A, and that it had no effect on breast cancer cell migration and colony formation, hormonal formulations containing the newer generation progestin DRSP may provide a better benefit/risk profile towards breast cancer than those containing the older generation progestins.

Progestin-primed ovarian stimulation: for whom, when and how?

Progestin-primed ovarian stimulation (PPOS) is being increasingly used for ovarian stimulation in assisted reproductive technology. Different progestins have been used with similar success. The available studies suggest a similar response to ovarian stimulation with gonadotrophin-releasing hormone (GnRH) analogues. Any differences in the duration of stimulation or gonadotrophin consumption are minor and clinically insignificant. PPOS has the advantage of oral administration and lower medication costs than GnRH analogues. As such it is clearly more cost-effective for fertility preservation and planned freeze-all cycles, but when fresh embryo transfer is intended PPOS can be less cost-effective depending on the local direct and indirect costs of the additional initial frozen embryo transfer cycle. Oocytes collected in PPOS cycles have similar developmental potential, including blastocyst euploidy rates. Frozen embryo transfer outcomes of PPOS and GnRH analogue cycles seem to be similar in terms of both ongoing pregnancy/live birth rates and obstetric and perinatal outcomes. While some studies have reported lower cumulative live birth rates with PPOS, they have methodological issues, including arbitrary definitions of the cumulative live birth rate. PPOS has been used in all patient types (except progesterone receptor-positive breast cancer patients) with consistent results and seems a patient friendly and cost-effective choice if a fresh embryo transfer is not intended.

A review of phase II and III drugs for the treatment and management of endometriosis.

INTRODUCTION: Endometriosis is an estrogen-dependent disease that gives rise to pelvic pain and infertility. Although estroprogestins and progestins currently stand as the first-line treatments for this condition, demonstrating efficacy in two-thirds of patients, a significant portion of individuals experience only partial relief or symptom recurrence following the cessation of these therapies. The coexistence of superficial, deep endometriosis, and ovarian endometriomas, as three distinct phenotypes with unique pathogenetic and molecular characteristics, may elucidate the current heterogeneous biological response to available therapy. AREAS COVERED: The objective of this review is to furnish the reader with a comprehensive summary pertaining to phase II-III hormonal treatments for endometriosis. EXPERT OPINION: Ongoing research endeavors are directed toward the development of novel hormonal options for this benign yet debilitating disease. Among them, oral GnRH antagonists emerge as a noteworthy option, furnishing rapid therapeutic onset without an initial flare-up; these drugs facilitate partial or complete estrogen suppression, and promote prompt ovarian function recovery upon discontinuation, effectively surmounting the limitations associated with previously employed GnRH agonists. Limited evidence supports the use of selective estrogen and progesterone receptor modulators. Consequently, further extensive clinical research is imperative to garner a more profound understanding of innovative targets for novel hormonal options.