Microglial-induced Müller cell gliosis is attenuated by progesterone in a mouse model of retinitis pigmentosa.

Norgestrel, a progesterone analogue, has demonstrated neuroprotective effects in a mouse model of retinitis pigmentosa. Neuroprotection is achieved in part through Norgestrels anti-inflammatory properties, alleviating detrimental microglial activity. Gliosis is a feature of many neurodegenerative diseases of the retina, including retinitis pigmentosa. Müller glia, a type of macroglia found in the retina, are major contributors of gliosis, characterized by the upregulation of glial fibrillary acidic protein (GFAP). Microglia-Müller glia crosstalk has been implicated in the initiation of gliosis. In the rd10 retina, increased microglial activity and gliotic events are observed prior to the onset of photoreceptor loss. We hypothesized that Norgestrels dampening effects on harmful microglial activity would consequently impact on gliosis. In the current study, we explore the role of microglia-Müller glia crosstalk in degeneration and Norgestrel-mediated neuroprotection in the rd10 retina. Norgestrels neuroprotective effects in the rd10 retina coincide with significant decreases in both microglial activity and Müller cell gliosis. Using a Müller glial cell line, rMC-1, and isolated microglia, we show that rd10 microglia stimulate GFAP production in rMC-1 cells. Norgestrel attenuates gliosis through direct actions on both microglia and Müller glia. Norgestrel reduces the release of harmful stimuli from microglia, such as interferon-γ, which might otherwise signal to Müller glia and stimulate gliosis. We propose that Norgestrel also targets Müller cell gliosis directly, by limiting the availability of pSTAT3, a known transcription factor for GFAP. These findings highlight an important aspect to Norgestrels neuroprotective effects in the diseased retina, in combating Müller cell gliosis.

Pro-survival redox signalling in progesterone-mediated retinal neuroprotection.

Retinitis pigmentosa (RP) is a group of hereditary retinal diseases, characterised by photoreceptor cell loss. Despite a substantial understanding of the mechanisms leading to cell death, an effective therapeutic strategy is sought. Our laboratory has previously demonstrated the neuroprotective properties of Norgestrel, a progesterone analogue, in the degenerating retina, mediated in part by the neurotrophic factor basic fibroblast growth factor (bFGF). In other retinal studies, we have also presented a pro-survival role for reactive oxygen species (ROS), downstream of bFGF. Thus, we hypothesized that Norgestrel utilises bFGF-driven ROS production to promote photoreceptor survival. Using the 661W photoreceptor-like cell line, we now show that Norgestrel, working through progesterone receptor membrane complex 1 (PGRMC1); generates an early burst of pro-survival bFGF-induced ROS. Using the rd10 mouse model of RP, we confirm that Norgestrel induces a similar early pro-survival increase in retinal ROS. Norgestrel-driven protection in the rd10 retina was attenuated in the presence of antioxidants. This study therefore presents an essential role for ROS signalling in Norgestrel-mediated neuroprotection in vitro and demonstrates that Norgestrel employs a similar pro-survival mechanism in the degenerating retina.

Metabolite Identification, Reaction Phenotyping, and Retrospective Drug-Drug Interaction Predictions of 17-Deacetylnorgestimate, the Active Component of the Oral Contraceptive Norgestimate.

Ortho Tri-Cyclen, a two-drug cocktail comprised of ethinylestradiol and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported. Hence, detailed biotransformation and reaction phenotyping studies of NGMN with recombinant cytochrome P450 (P450), recombinant uridine 5'-diphospho-glucuronosyltransferases, and human liver microsomes in the presence and absence of selective P450 inhibitors were conducted. It was found that CYP3A4 plays a key role in NGMN metabolism with a fraction metabolized (fm) of 0.57. CYP2B6 and to an even lesser extent CYP2C9 were also observed to catalyze NGMN metabolism. Using this CYP3A4 fm value, the predicted plasma concentration versus time area under the curve (AUC) change in NGMN using a basic/mechanistic static model was found to be within 1.3-fold of the reported NGMN AUC changes for four modulators of CYP3A4. In addition to NGMN, we have also elucidated the biotransformation of norgestrel (NG), a downstream norgestimate and NGMN metabolite, and found that CYP3A4 and UGT1A1 have a major contribution to the elimination of NG with a combined fm value of 1. The data presented in this paper will lead to better understanding and management of NGMN-based drug-drug interactions when norgestimate is coadministered with CYP3A4 modulators.

Progesterone receptor signalling in retinal photoreceptor neuroprotection.

'Norgestrel', a synthetic form of the female hormone progesterone has been identified as potential drug candidate for the treatment of the degenerative eye disease retinitis pigmentosa. However, to date, no work has looked at the compound's specific cellular target. Therefore, this study aimed to identify the receptor target of Norgestrel and begin to examine its potential mechanism of action in the retina. In this work, we identify and characterize the expression of progesterone receptors present in the C57 wild type and rd10 mouse model of retinitis pigmentosa. Classical progesterone receptors A and B (PR A/B), progesterone receptor membrane components 1 and 2 (PGRMC1, PGRMC2) and membrane progesterone receptors α, ß and γ were found to be expressed. All receptors excluding PR A/B were also found in the 661W photoreceptor cell line. PGRMC1 is a key regulator of apoptosis and its expression is up-regulated in the degenerating rd10 mouse retina. Activated by Norgestrel through nuclear trafficking, siRNA knock down of PGRMC1 abrogated the protective properties of Norgestrel on damaged photoreceptors. Furthermore, specific inhibition of PGRMC1 by AG205 blocked Norgestrel-induced protection in stressed retinal explants. Therefore, we conclude that PGRMC1 is crucial to the neuroprotective effects of Norgestrel on stressed photoreceptors. The synthetic progestin 'Norgestrel' has been identified as a potential therapeutic for the treatment of Retinitis Pigmentosa, a degenerative eye disease. However, the mechanism behind this neuroprotection is currently unknown. In this work, we identify 'Progesterone Receptor Membrane Component 1' as the major progesterone receptor eliciting the protective effects of Norgestrel, both in vitro and ex vivo. This furthers our understanding of Norgestrel's molecular mechanism, which we hope will help bring Norgestrel one step closer to the clinic.

The synthetic progesterone Norgestrel is neuroprotective in stressed photoreceptor-like cells and retinal explants, mediating its effects via basic fibroblast growth factor, protein kinase A and glycogen synthase kinase 3ß signalling.

The synthetic progesterone Norgestrel has been shown to have proven neuroprotective efficacy in two distinct models of retinitis pigmentosa: the rd10/rd10 (B6.CXBI-Pde6b(rd10)/J) mouse model and the Balb/c light-damage model. However, the cellular mechanism underlying this neuroprotection is still largely unknown. Therefore, this study aimed to examine the downstream signalling pathways associated with Norgestrel both in vitro and ex vivo. In this work, we identify the potential of Norgestrel to rescue stressed 661W photoreceptor-like cells and ex vivo retinal explants from cell death over 24 h. Norgestel is thought to work through an upregulation of neuroprotective basic fibroblast growth factor (bFGF). Analysis of 661W cells in vitro by real-time polymerase chain reaction (rt-PCR), enzyme-linked immunosorbent assay (ELISA) and Western blotting revealed an upregulation of bFGF in response to Norgestrel over 6 h. Specific siRNA knockdown of bFGF abrogated the protective properties of Norgestrel on damaged photoreceptors, thus highlighting the crucial importance of bFGF in Norgestrel-mediated protection. Furthermore, Norgestrel initiated a bFGF-dependent inactivation of glycogen synthase kinase 3ß (GSK3ß) through phosphorylation at serine 9. The effects of Norgestrel on GSK3ß were dependent on protein kinase A (PKA) pathway activation. Specific inhibition of both the PKA and GSK3ß pathways prevented Norgestrel-mediated neuroprotection of stressed photoreceptor cells in vitro. Involvement of the PKA pathway following Norgestrel treatment was also confirmed ex vivo. Therefore, these results indicate that the protective efficacy of Norgestrel is, at least in part, due to the bFGF-mediated activation of the PKA pathway, with subsequent inactivation of GSK3ß.

The synthetic progestin norgestrel acts to increase LIF levels in the rd10 mouse model of retinitis pigmentosa.

PURPOSE: Retinal degenerative conditions affect thousands of people worldwide. Retinitis pigmentosa (RP) is among the most common, but it is currently incurable. It is characterized by the progressive death of photoreceptor cells, eventually leading to blindness. Neurotrophic factors play an important role in such retinopathies, and much research has been performed on their use as treatments. Our group previously demonstrated the ability of the synthetic progestin norgestrel to rescue photoreceptors from cell death, the mechanism of which is believed to include upregulation of the neurotrophic factor basic fibroblast growth factor (bFGF). The objective of the present study was to investigate whether the protection provided by norgestrel is likely to be mediated by other neurotrophins. METHODS: The 661W photoreceptor cells and retinal explants from P30 to P40 wild-type (wt) C57BL/6 mice were treated with norgestrel over time. Homozygous rd10/rd10 mice that mimic the human form of RP were fed either a control or a norgestrel-containing diet. Changes in neurotrophic factor expression in response to norgestrel were detected with real-time PCR, western blotting, or immunofluorescence staining. Using specific siRNA, leukemia inhibitory factor (Lif) expression was knocked down in 661W photoreceptor cells that were stressed by serum starvation. Cells were treated with norgestrel followed by measurement of cell viability with (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay. RESULTS: LIF, a potent neuroprotective cytokine, was found to be upregulated in response to norgestrel in vitro and in vivo. Upregulation of LIF in degenerating rd10 retinas coincided with preservation of the photoreceptor layer. We also found LIF was necessary for the norgestrel-mediated rescue of stressed photoreceptor cells from cell death in vitro. CONCLUSIONS: LIF was upregulated in response to norgestrel in all models studied and is necessary for the protective effects of norgestrel in vitro. The increase in LIF expression in rd10 mice undergoing retinal degeneration was concurrent with rescue of the photoreceptor cell layer. These results highlight the ability of norgestrel to induce prosurvival molecules in the compromised retina, underlining norgestrel's potential as a viable drug for treatment of RP.

A positive feedback loop between progesterone and microsomal prostaglandin E synthase-1-mediated PGE2 promotes production of both in mouse granulosa cells.

Microsomal prostaglandin E synthase-1 (mPGES-1) is primarily expressed in granulosa cells (GCs) in the preovulatory follicle. Both prostaglandin E2 (PGE2) and progesterone (P4) are implicated in various reproductive functions. Here, we demonstrate that mPges-1 may be a direct downstream target gene of the P4 receptor and P4-stimulated PGE2 secretion can stimulate P4 production in a newly generated mouse GC line (GtsT). Treatment of GtsT cells with a P4 receptor agonist, norgestrel, markedly increased mPGES-1 expression detected by RT-PCR analysis. PGE2 secretion measured by an enzyme-linked immunosorbent assay was enhanced by P4 treatment. Luciferase assays revealed that the proximal promoter region of the mPges-1 gene was responsible for the effects of P4 treatment. Conversely, PGE2 treatment stimulated P4 secretion, which coordinated with mRNA expression of steroidogenic acute regulatory protein. Taken together, P4 may regulate mPGES-1 expression to increase PGE2 secretion and in turn P4 production. An autocrine loop between P4 and PGE2 might function to maintain the increased levels of both in GCs.

Molecular action of norgestimate: new developments.

BACKGROUND: Acne occurs because the sebaceous glands are overstimulated by high levels of androgens or are hypersensitive to normal levels of testosterone. In women with mild or moderate acne, the association of norgestimate (NG), and ethinyl estradiol (EE) is an effective treatment. This is related to the effect of oral contraceptives on androgen production and transport and the antiandrogenic properties of NG itself. DESIGN: The present work was undertaken to find out whether NG and its derivative, 17-deacetylnorgestimate(dNG), present steroid activities other than antiandrogen activities, using human progesterone receptor(PR), estrogen receptor α(ERα) and ß(ERß), glucocorticoid receptor(GR) and mineralocorticoid receptor(MR)-responsive cell lines. RESULTS: We confirmed that NG and its metabolite were progestogen partial agonists (EC50 of 13 and 11.1 nM) and ERα selective agonists (EC50 of 30.4 and 43.4 nM), as well as full antagonists of low affinity for GR (IC50 of 325 and 255 nM) and moderate affinity for MR (IC50 of 81.2 and 83.7). CONCLUSION: We demonstrated that NG and dNG have full progestogen and weak estrogenic (through ERα) properties, which could explain in part the efficacy of NG in association with EE for the treatment of moderate acne in women. Moreover, their antagonist MR activity might have a favorable impact on cardiovascular risk, atherosclerosis and lipid profiles.

Progestins activate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells.

PFKFB (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) catalyses the synthesis and degradation of Fru-2,6-P2 (fructose-2,6-bisphosphate), a key modulator of glycolysis and gluconeogenesis. The PFKFB3 gene is extensively involved in cell proliferation owing to its key role in carbohydrate metabolism. In the present study we analyse its mechanism of regulation by progestins in breast cancer cells. We report that exposure of T47D cells to synthetic progestins (ORG2058 or norgestrel) leads to a rapid increase in Fru-2,6-P2 concentration. Our Western blot results are compatible with a short-term activation due to PFKFB3 isoenzyme phosphorylation and a long-term sustained action due to increased PFKFB3 protein levels. Transient transfection of T47D cells with deleted gene promoter constructs allowed us to identify a PRE (progesterone-response element) to which PR (progesterone receptor) binds and thus transactivates PFKFB3 gene transcription. PR expression in the PR-negative cell line MDA-MB-231 induces endogenous PFKFB3 expression in response to norgestrel. Direct binding of PR to the PRE box (-3490 nt) was confirmed by ChIP (chromatin immunoprecipiation) experiments. A dual mechanism affecting PFKFB3 protein and gene regulation operates in order to assure glycolysis in breast cancer cells. An immediate early response through the ERK (extracellular-signal-regulated kinase)/RSK (ribosomal S6 kinase) pathway leading to phosphorylation of PFKFB3 on Ser461 is followed by activation of mRNA transcription via cis-acting sequences on the PFKFB3 promoter.

Impact of combined oral contraceptives containing ethinylestradiol on the liver microsomal metabolism.

OBJECTIVES: To check whether currently used combined oral contraceptives (COCs) containing ethinylestradiol (EE) affect the liver microsomal metabolism. METHODS: (13)C-methacetin breath test ((13)C-MBT) - a sensitive non-invasive probe of cytochrome P-450 1A2 activity - was performed in 15 women on day 14, 15, 16, 17 or 18 of intake of their COC (containing EE), and between day 1 and 5 during the withdrawal bleeding, as well as in nine women not using hormonal contraception during the luteal phase of their cycle (between the 17th and the 23rd day), and between day 1 and 5 during menstruation. RESULTS: The maximum breath (13)C elimination was significantly lower during the phase of intake of contraceptive pills than during withdrawal bleeding: 31.5 ± 2.2 %/h vs. 38.2 ± 1.9 %/h (p = 0.0045), whereas the time to reach it was similar on the two study days: 21.2 ± 1.2 min vs. 21.0 ± 1.1 min. Between the 27th and the 180th min of observation the cumulative breath (13)C elimination was statistically significantly lower during intake of the pill than during withdrawal bleeding. No significant menstrual cycle phase-dependent fluctuations in the results of the (13)C- methacetin breath test were observed in the control group. CONCLUSION: COCs containing EE markedly inhibit hepatic microsomal function. This phenomenon must be taken into consideration when interpreting results of (13)C-MBT.

Hormone withdrawal-associated symptoms: comparison of oestradiol valerate/dienogest versus ethinylestradiol/norgestimate.

OBJECTIVES: To determine the effect of oestradiol valerate/dienogest (E2V/DNG) versus ethinylestradiol/norgestimate (EE/NGM) on hormone-withdrawal associated symptoms (HWAS) in otherwise healthy women who had experienced at least one of these symptoms when using 21/7-day combined oral contraceptives (COCs). METHODS: This phase III, parallel-group study randomised 409 women aged 18 to 50 years to E2V/DNG or EE/NGM. The primary efficacy variable was the change from baseline to cycle 6 in the average of the three highest visual analogue scale values for headache and/or pelvic pain during cycle days 22 to 28. RESULTS: In total, 395 were included in the full analysis set (E2V/DNG, n = 191; EE/NGM, n = 204). E2V/DNG reduced the symptoms of headache or pelvic pain during cycle days 22 to 28 from baseline to cycle 6 to a significantly greater extent than EE/NGM (mean decrease 43.6 vs. 35.5 mm; p = 0.0024). Both treatments were well tolerated with a similar proportion of women experiencing adverse events that were considered at least possibly related to treatment (35% E2V/DNG vs. 34% EE/NGM). CONCLUSIONS: E2V/DNG reduces the frequency and intensity of headache and pelvic pain to a greater extent than EE/NGM, and may be a good option for women susceptible to HWAS with conventional 21/7-day COCs.

Norgestrel causes digestive gland injury in the clam Mactra veneriformis: An integrated histological, transcriptomics, and metabolomics study.

The potential adverse effects of progestins on aquatic organisms, especially non-target species, are of increasing concern worldwide. However, the effect and mechanism of progestin toxicity on aquatic invertebrates remain largely unexplored. In the present study, clams Mactra veneriformis were exposed to norgestrel (NGT, 0, 10, and 1000 ng/L), the dominant progestin detected in the aquatic environment, for 21 days. NGT accumulation, histology, transcriptome, and metabolome were assessed in the digestive gland. The bioconcentration factor (BCF) was 386 and 268 in the 10 ng/L NGT group and 1000 ng/L NGT group, respectively, indicating efficient accumulation of NGT in the clams. Histological analysis showed that NGT led to the swelling of epithelial cells and blurring of the basement membrane in the digestive gland. Differentially-expressed genes and KEGG pathway enrichment analysis using a transcriptomic approach suggested that NGT primarily disturbed the detoxification system, antioxidant defense, carbohydrate and amino acid metabolism, and steroid hormone metabolism, which was consistent with the metabolites analyzed using a metabolomic approach. Furthermore, we speculated that the oxidative stress caused by NGT resulted in histological damage to the digestive gland. This study showed that NGT caused adverse effects in the clams and sheds light on the mechanisms of progestin interference in aquatic invertebrates.

Synergistic effects of EP-1 and ivermectin mixture (iEP-1) to control rodents and their ectoparasites.

BACKGROUND: Ectoparasites of rodents play significant roles in disease transmission to humans. Conventional poisoning potentially reduces the population densities of rodents, however, they may increase the ectoparasite loads on the surviving hosts. EP-1 has been shown to have anti-fertility effects on many rodent species, while ivermectin is effective in controlling ectoparasites. In this study, we examined the combined effects of EP-1 and ivermectin mixture (iEP-1) baits on rodents and their corresponding flea/tick loads. RESULTS: In males, the weight of testis, epididymis, and seminiferous vesicle were reduced to less than 33%, 25%, and 17%, respectively, compared to the control group following administration of iEP-1 for 7 days. The weight of the uterus increased by approximately 75%. After 5 days of iEP-1 intake, all ticks were killed, whereas 94% of fleas on mice died after 3 days of bait intake. In the field test near Beijing, the flea index was reduced by more than 90% after 7 days of iEP-1 bait delivery. In a field test in Inner Mongolia, the weights of testis, epididymis, and seminiferous vesicle were significantly reduced by 27%, 32%, and 57%, respectively, 2 weeks after iEP-1 bait delivery. Approximately 36% rodents exhibited obvious uterine oedema accompanied by a weight increase of about 150%. The flea index was reduced by over 90%. CONCLUSION: Our results indicated that iEP-1 is a promising treatment for reducing the abundance of both small rodents and their ectoparasites; this will be effective for managing rodent damage and transmission of rodent-borne diseases associated with fleas and ticks. © 2022 Society of Chemical Industry.

In vitro exposure to environmentally relevant concentrations of norgestrel affects sperm physiology and reproductive success of the Pacific oyster Crassostrea gigas.

Progestins in aquatic environments are of increasing concern, as shown by the results of toxicological studies on adult invertebrates with external fertilization. However, their potential effects on the gametes and reproductive success of such animals remain largely unknown. Thus, the current study assessed the effect of in vitro exposure of environmentally relevant concentrations (10 ng/L and 1000 ng/L) of norgestrel (NGT) on the sperm of Pacific oyster Crassostrea gigas, analyzing sperm motility, ultrastructure, mitochondrial function, ATP status, characteristic enzyme activities, and DNA integrity underlying fertilization and hatching success. The results showed that NGT increased the percentage of motile sperm by elevating intracellular Ca2+ levels, Ca2+-ATPase activity, creatine kinase activity, and ATP content. Although superoxide dismutase activity was enhanced to eliminate reactive oxygen species generated by NGT, oxidative stress occurred, as indicated by the increase in malonaldehyde content and damage to plasma membranes and DNA. As a consequence, fertilization rates decreased. However, hatching rates did not alter significantly, possibly as a result of DNA repair processes. This study demonstrates oyster sperm as a useful, sensitive tool for toxicological research of progestins and provides ecologically relevant information on reproductive disturbance in oysters resulting from exposure to NGT.

Enhancing survival of photoreceptor cells in vivo using the synthetic progestin Norgestrel.

Retinal degenerations such as Retinitis Pigmentosa remain difficult to treat given the diverse array of genes responsible for their aetiology. Rather than concentrate on specific genes, our focus is on identifying therapeutic avenues for the treatment of retinal disease that target general survival mechanisms or pathways. Norgestrel is a synthetic progestin commonly used in hormonal contraception. Here, we report a novel anti-apoptotic role for Norgestrel in diseased mouse retinas in vivo. Dosing with Norgestrel protects photoreceptor cells from undergoing apoptosis in two distinct models of retinal degeneration; the light damage model and the Pde6b(rd10) model. Photoreceptor rescue was assessed by analysis of cell number, structural integrity and function. Improvements in cell survival of up to 70% were achieved in both disease models, indicating that apoptosis had been halted or at least delayed. A speculative mechanism of action for Norgestrel involves activation of survival pathways in the retina. Indeed, Norgestrel increases the expression of basic fibroblast growth factor which is known to both promote cell survival and inhibit apoptosis. In summary, our results demonstrate significant protection of photoreceptor cells which may be attributed to Norgestrel mediated activation of endogenous survival pathways within the retina.

High levels of women's satisfaction and compliance with transdermal contraception: results from a European multinational, 6-month study.

OBJECTIVE: To investigate compliance, satisfaction, and preference in women using a transdermal contraceptive patch. METHODS: Women (18-46 years) from eight European countries used contraceptive patches (norelgestromin 6 mg, ethinylestradiol 600 µg) for six, 4-week treatment cycles. Compliance, satisfaction, and preference were assessed after 3 and 6 cycles and study completion using self-report methods. RESULTS: Of the 778 participants, 36.8% (n = 287) used no contraception at baseline. The most common methods were oral contraceptives (67.9%, n = 334) and barrier methods (21.5%, n = 106). Of oral contraception users, 63.5% (n = 212) were satisfied or very satisfied with their previous method, but compliance was poor with 77.8% (n = 260) reporting missed doses. After 3 and 6 cycles, >80% of all included women were satisfied or very satisfied with the patch. At study completion, most participants (73.7%) reported a preference for the patch compared to their previous method. Of 4107 cycles, 3718 (90.5%) were completed with perfect compliance. Two pregnancies occurred during this study, representing a Pearl Index of 0.63. No new safety issues were identified and the patch was well tolerated. CONCLUSION: Women were highly satisfied with transdermal contraception and preferred this form of family planning over their previous method. Transdermal contraception represents a valuable addition to contraceptive options with potential to offer high compliance and efficacy.

The paradigm of norgestimate: a third-generation testosterone-derivative progestin with a peripheral anti-androgenic activity and the lowest risk of venous thromboembolism.

INTRODUCTION: Norgestimate (NGM) is a testosterone derivative with peculiar receptor activities. AREAS COVERED: This is a narrative review of the available data on the pharmacotherapy of NGM in combined hormonal contraceptives (CHCs) in terms of contraceptive efficacy, venous thromboembolism (VTE) risk, safety, tolerability and bleeding patterns. A comprehensive literature review was conducted in August 2020 using PubMed with the keyword 'norgestimate'. EXPERT OPINION: NGM shows a mild estrogenic activity associated with anti-mineralocorticoid and anti-androgenic properties, largely responsible for the cardiovascular safety profile. The anti-androgenic property depends on the androgen receptor (AR) nuclear translocation (AR trafficking and its subnuclear distribution), the inhibition of 5α-reductase activity (it possesses higher activity compared to other available progestins), and the increase on sexual hormone binding globulin (SHBG) levels if combined with an estrogenic counterpart. NGM is one of the molecules that best modulates the power of ethinyl-estradiol on the thromboembolic risk, being associated with the lowest VTE risk between different CHCs. NGM has the advantage of retaining peripheral anti-androgenic activity, demonstrated by the impact on lipid and glucose metabolism, and it should be preferred if compared with other similar progestins of the same class of risk which are much more androgenic, such as levonorgestrel.

[Combined hormonal contraception in cycles artificially extended]. / Anticoncepción con hormonales combinados en ciclos extendidos artificialmente.

OBJECTIVE: To compare the bleeding patterns, satisfaction and tolerability of 3 different contraceptive in an extended regimens in the service of Family Planning of the North Central Hospital of PEMEX. MATERIAL AND METHODS: Healthy, adult women with desire of contraception for one year (N 120) were randomly assigned to receive oral contraceptive drospirenone/ethinyl E2 (group1), the norelgestromin/ethinyl E2 transdermal patch (group 2) and vaginal ring etonogestrel/ ethinyl E2 (group 3) in an extended regimen (42 consecutive days, 1 hormone-free week). Study assessments were conducted at scheduled visits at the time of initial screening, at baseline after 1, 3, 6, and 12 months. Subjects recorded menstrual associated symptoms bleeding data and completed satisfaction questionnaires. Subjects and investigators provided overall assessments of the regimens. RESULTS: Extended use of 3 different contraceptive resulted in fewer bleeding days in every group (66.6%, 55% and 58.3% P 0.0024), and less mastalgia and menstrual pain. Subjects were highly satisfied with three regimens (93.3%, 96.6% and 91.6% P 0.00421). Although not mayor adverse events were reported with this regimen, there was an increase in spotting days; it decreased with each successive cycle of therapy. Efficacy and safety were similar to those reported for traditional cycle. CONCLUSION: Extended-contraceptive regimen delays menses and reduces bleeding, a profile that may be preferred by women who seek flexibility with their contraceptive method.

Norgestrel, a Progesterone Analogue, Promotes Significant Long-Term Neuroprotection of Cone Photoreceptors in a Mouse Model of Retinal Disease.

Purpose: Retinitis pigmentosa (RP) refers to a group of inherited blinding retinal diseases, whereby the death of mutated rod photoreceptors is followed closely by the death of cone photoreceptors. Cone cell death can be hugely debilitating as color/daytime vision becomes impaired. Thus, treatments that are effective against cone cell death are urgently needed. Our research has been working toward development of a neuroprotective treatment for RP. We have previously demonstrated significant neuroprotective properties of norgestrel, a progesterone analogue, in the mouse retina. The current study further investigates the potential of norgestrel as a treatment for RP, with a focus on long-term preservation of cone photoreceptors. Methods: Using the well-established rd10 mouse model of RP, we administered a norgestrel-supplemented diet at postnatal day (P)30, following widespread loss of rod photoreceptors and at the outset of cone degeneration. We subsequently assessed cone cell morphology and retinal function at P50, P60, and P80, using immunohistochemistry, electroretinograph recordings, and optomotor testing. Results: While cone cell degeneration was widespread in the untreated rd10 retina, we observed profound preservation of cone photoreceptor morphology in the norgestrel-treated mice for at least 50 days, out to P80. This was demonstrated by up to 28-fold more cone arrestin-positive photoreceptors. This protection transpired to functional preservation at all ages. Conclusions: This work presents norgestrel as an incredibly promising long-term neuroprotective compound for the treatment of RP. Crucially, norgestrel could be used in the mid-late stages of the disease to protect remaining cone cells and help preserve color/daytime vision.

A Multi-Center, Open-Label, Pharmacokinetic Drug Interaction Study of Erenumab and a Combined Oral Contraceptive in Healthy Females.

BACKGROUND: Erenumab is a human anti-calcitonin gene-related peptide monoclonal antibody developed for migraine prevention. Migraine predominately affects women of childbearing age; thus, it is important to determine potential drug-drug interactions between a common oral contraceptive and drugs used to treat migraine. OBJECTIVES: We sought to evaluate potential drug-drug interactions between erenumab and a common oral contraceptive. METHODS: Healthy women received three cycles of a norgestimate/ethinyl estradiol-containing oral contraceptive with a single 140-mg subcutaneous dose of erenumab during cycle three. Norgestimate metabolites (norgestrel and norelgestromin) and ethinyl estradiol pharmacokinetics were evaluated in the absence and presence of erenumab. Primary endpoint was peak plasma concentration (Cmax) and area under concentration-time curve from time 0 to 24 h (AUCtau). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were evaluated as pharmacodynamic markers. RESULTS: Erenumab did not influence the pharmacokinetics of norelgestromin, norgestrel, or ethinyl estradiol. Least-squares mean estimates (90% confidence interval) for Cmax ratios were 1.05 (0.90-1.23), 1.06 (0.97-1.16), and 1.04 (0.88-1.22) for norelgestromin, norgestrel, and ethinyl estradiol, respectively. Respective AUCtau ratios were 1.02 (0.94-1.12), 1.03 (0.96-1.10), and 1.02 (0.91-1.14). Luteinizing hormone, follicle-stimulating hormone, and progesterone concentrations were similar after exposure to oral contraceptive alone and with erenumab. CONCLUSION: Erenumab did not alter the pharmacokinetics of the active components of an estrogen/progestin combination oral contraceptive. Thus, no change in contraceptive efficacy is expected with erenumab. TRIAL REGISTRATION: ClinicalTrials.gov NCT02792517.