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Objectives: To develop a model to estimate the possible impact of use of an over-the-counter (OTC) progestin-only pill (POP) on the number of unintended pregnancies in the United States.Study Design: Using typical use failure rates (7% for POPs), we compared the expected number of unintended pregnancies for two theoretical cohorts of 100,000 women: one which purchased and used an OTC POP exclusively for contraception, the other using contraceptive methods at proportions obtained from an actual-use clinical trial simulating OTC use of norgestrel 0.075 mg (including 35% using no method and only 19% using hormonal contraception or long-acting contraceptives). Sensitivity analyses were conducted using alternative model inputs such as different failure rates for OTC POPs and varied alternative contraceptive method mix.Results: An estimated 37,624 unintended pregnancies would occur annually if 100,000 women continued their usual contraceptive method as used at baseline in the actual use trial. This would be reduced by 81% to 7,000 pregnancies with the exclusive use of an OTC POP - a net reduction of 30,624 unintended pregnancies annually. While the number of unintended pregnancies prevented varied as the model parameters were modified (ranging from 1,461 to 34,124), a net benefit of OTC POP use was observed over a wide range of input values.Conclusions: Using data from a real-world contraception user profile, our model suggests that use of an OTC POP could reduce the overall number of unintended pregnancies in the United States. This conclusion remains true across a wide range of modeled scenarios.Implications: The estimates suggested by this model are supportive of an OTC switch for a POP. [ABSTRACT FROM AUTHOR]

Progestins are crucial steroid hormones that have attracted wide attention due to their endocrine disrupting effects in fish. The aim of this study is to investigate the effects of long-term exposure to low concentrations of norgestrel (NGT) on the reproductive and thyroid endocrine systems of adult zebrafish. Adult zebrafish were exposed to 7 and 39 ng/L NGT for a duration of 90 days. The results revealed that exposure to 39 ng/L NGT led to a significant up-regulation of 3β-hydroxysteroid dehydrogenase (hsd3b) and 20β-hydroxysteroid dehydrogenase (hsd20b) genes in the ovary of female zebrafish. Additionally, there was a significant up-regulation of 11β-hydroxysteroid dehydrogenase 2 (hsd11b2) gene in the testis of male zebrafish. Furthermore, egg production decreased significantly, accompanied by notable alterations in the proportion of ovarian development stages, as well as reductions of sex hormone levels (E2, 11-KT, and T) in both females and males. However, long-term exposure to low concentrations of NGT did not lead to changes in thyroid hormone levels and thyroid histopathology in adult zebrafish. The overall results imply that environmental concentrations of NGT have a strong endocrine disrupting effect on the reproductive system of zebrafish, while the thyroid system is not sensitive to NGT exposure. The present study underscores the reproductive endocrine impacts of NGT and emphasizes the necessity for prolonged exposure at environmental concentrations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To evaluate the cervical mucus effects of a norgestrel 0.075 mg progestin-only contraceptive pill over a 28-day cycle.Study Design: We recruited persons ages 18 to 35 with normal cycles at 2 US academic medical centers. Participants took norgestrel 0.075 mg daily for 28 days at the same time (within a 3 hour window) daily, recorded through a text-message based e-diary. We extracted cervical mucus using a standardized aspiration technique on the day of pill initiation and then at least every 3 to 4 days over the cycle. We monitored subjects for follicular activity with transvaginal ultrasound examination and blood sampling for ovarian hormones and gonadotropins at each visit. We assessed cervical mucus scoring using a 4-category/12-point modified Insler scale (score ≥9 [favoring fertility], 5-8 [intermediate], and ≤4 [unfavorable to fertility]). We stratified cervical mucus scores by serum estradiol levels and ovulatory status based on a modified Hoogland score.Results: Excluding enrollment, we collected and evaluated 413 mucus samples from 51 participants. Participants had a median mucus score of 0 (Interquartile Range 0, 2); most had scores ≤4 (samples = 385, 93%) and none had a score ≥9 favoring fertility. Seventeen (33%) participants ovulated, of which 14 (82%) had unfavorable mucus scores (≤4) at the time of ovulation and 3 (18%) had intermediate scores (5-8).Conclusions: Norgestrel 0.075 mg daily prevents mucus changes that favor fertility, even during ovulatory cycles.Implications: Daily administration of norgestrel 0.075 mg over an initial 28-day cycle did not result in fertile cervical mucus. Although approximately one-third of users ovulated in this first cycle of pill use, contraceptive efficacy may be maintained by mucus effects. [ABSTRACT FROM AUTHOR]

Objectives: To review published data on the effectiveness of a progestogen-only pill containing norgestrel 75 µg/day which should be under consideration by the FDA in 2022 for sale over the counter in the US.Study Design: A literature search in MEDLINE, EMBASE, and COCHRANE REVIEWS using specified search terms and adding related cross-references.Results: We identified a total of thirteen relevant studies of women using norgestrel 75 µg/day. None were reported with the rigor characteristic of trial reporting today. Nevertheless, six studies provided data on 3,184 women who were not breastfeeding, followed for over 35,000 months and reported a range of overall failure rates during typical use of norgestrel 75 µg/day from 0 to 2.4/hundred woman-years giving an aggregate Pearl Index of 2.2. Seven additional studies involved 5,445 women some of whom were breastfeeding for at least part of the period of follow-up. More than 36,000 months of use yielded 12-month life table cumulative pregnancy rates for norgestrel 75 µg/day ranging from 0 to 3.4. We were unable to calculate an aggregate Pearl Index for the breastfeeding studies because of lack of crucial data.Conclusions: The data support that norgestrel 75 µg/day is highly effective in clinical use, with similar estimates of failure in breastfeeding and non-breastfeeding women, providing support to the case for approval without the need to see a healthcare provider. [ABSTRACT FROM AUTHOR]

In an effort to switch a norgestrel 0.075 mg progestin-only pill (Opill) from prescription to over-the-counter, we conducted this study to assess whether consumers can use the drug facts label alone to guide appropriate self-selection. Two studies assessed self-selection: (1) an all-comers, actual-use study evaluating self-selection before purchasing and using norgestrel 0.075 mg and (2) the Targeted Breast Cancer Self-Selection Study evaluating theoretical self-selection among participants with a history of breast cancer. In the actual-use study, based on the label, 1670/1772 participants (94%) were appropriate for use of norgestrel 0.075 mg; 102 (6%) were not appropriate. Of the 102, 66 (65%) correctly did not select and 36 (35%) responded it was okay for them to use norgestrel 0.075 mg. Of the 36 participants who incorrectly self-selected, one had a history of breast cancer and thus might have been adversely affected had they taken norgestrel 0.075 mg. In the Targeted Breast Cancer Self-Selection Study (N = 206), 97% of participants correctly stated norgestrel 0.075 mg was not appropriate for them. The proposed over-the-counter label enables 98% of potential users to self-select norgestrel 0.075 mg appropriately. Only 2% of potential purchasers may have bought and started to use norgestrel 0.075 mg inappropriately. For two-thirds of these, the potential benefits of their use of the method outweighed any theoretical risks. Adverse clinical consequences of norgestrel 0.075 mg use are unlikely even in those rare cases when the drug facts label was not followed. The balance of the risk of inappropriate selection to the benefit of taking an over-the-counter progestin-only pill appears to be very much in favor of an overall benefit in terms of unintended pregnancy prevention. [ABSTRACT FROM AUTHOR]

The Adherence with Continuous Dose Oral Contraceptive: Evaluation of Self-Selection and Use (ACCESS) study assessed whether consumers can adhere to the regimen for a progestin-only pill (norgestrel 0.075 mg) in an over-the-counter (OTC) setting. An actual use study in a simulated OTC environment assessed adherence to directions to take norgestrel 0.075 mg every day at the same time in 883 participants for up to 24 weeks. Eighty-five percent (747/883) of participants reported ≥85% adherence to taking norgestrel 0.075 mg every day and reported taking their dose within three hours of their scheduled dosing time on 96% of days. When accounting for use of a condom for 48 hours if a pill was missed, participants reported correctly following the label's directed use for 97% of doses overall, with 95% of participants following label directions for ≥85% of doses. The main limitations were related to finding a balance between intensely collecting data to ensure accurate assessment of adherence and leaving users to behave as they would in a real OTC situation without healthcare practitioner intervention. We observed that some participants reported taking more doses than they could have based on the supply of medication given to them. To fully examine the situation, and the impact on the conclusions, additional post hoc sensitivity analyses were performed, and showed remarkably consistent results. Consumers were highly adherent to taking norgestrel 0.075 mg when using only the information provided by the proposed OTC label. Adherence to a daily oral contraceptive pill was high when obtained OTC. This suggests that effectiveness of an OTC pill is likely to be like that of a prescribed pill and easier access to this effective contraceptive should allow more opportunity to prevent pregnancy. [ABSTRACT FROM AUTHOR]

Purpose: To examine whether there is a positive association between sexual dysfunction (SD) and different types of progestin-based contraceptives. Methods: Nested case-control study in women of child-bearing age (15–45 years) from the IQVIA® Ambulatory electronic medical record database from 2008 to 2018. Cases defined by diagnosis of sexual dysfunction identified by international classification for disease clinical modification code 9th and 10th. Each case was matched to four controls and rates of prescriptions of the following were compared: levonorgestrel intra-uterine device (IUD), progestin, and ethinyl estradiol (EE) combined oral contraceptive (COC) formulations including levonorgestrel, norgestimate, drospirenone, desogestrel, norethindrone, and norgestrel; etonogestrel vaginal ring; and medroxyprogesterone injection. Results: Overall, 6689 cases of patients with SD were matched to 26,756 matched controls. Compared with matched controls, more subjects with SD used levonorgestrel IUD (OR 1.24, 95% CI 1.08–1.44), EE-levonorgestrel COC (OR 1.18, 95% CI 1.00–1.41), EE-drospirenone (OR 1.28, 95% CI 1.00–1.67), and medroxyprogesterone (OR 1.38, 95% CI 1.12–1.70). The use of norgestrel exhibited a protective effect (OR 0.83, 95% CI 0.73–0.95). When using the EE-levonorgestrel COC as a comparator, norgestrel users exhibited a protective effect (OR 0.70, 95% CI 0.57–0.87) while no other contraceptives showed a statistically significant difference in association with SD. Conclusion: Our study found an increase in the use of levonorgestrel (COC and IUD), drospirenone, and medroxyprogesterone in subjects with SD. The risk of contraceptives did not differ when compared with oral levonorgestrel. The small association size and lack of difference between drug formulations suggest a minimal impact of progestin-based contraceptives on sexual dysfunction. [ABSTRACT FROM AUTHOR]

Just less than half of the pregnancies in the United States are unintended. Unintended pregnancy rates are greatest among women younger than 24 years, women of color, and those who have incomes less than 200% of the federal poverty level. Additionally, options to terminate a pregnancy are restricted or limited in some states. In July 2023, the U.S. Food and Drug Administration approved norgestrel (Opill) as the first over-the-counter oral contraceptive pill available in the United States. Norgestrel is indicated specifically for the prevention of pregnancy, contains only progesterone, and is indicated for daily oral use. This article provides an overview of over-the-counter norgestrel, including administration, adverse effects, contraindications, and practice implications for women's health nurses., (Copyright © 2024 AWHONN. Published by Elsevier Inc. All rights reserved.)

Retinitis pigmentosa (RP) is one of the most common retinal degenerative conditions affecting people worldwide, and is currently incurable. It is characterized by the progressive loss of photoreceptors, in which the death of rod cells leads to the secondary death of cone cells; the cause of eventual blindness. As rod cells die, retinal-oxygen metabolism becomes perturbed, leading to increased levels of reactive oxygen species (ROS) and thus oxidative stress; a key factor in the secondary death of cones. In this study, norgestrel, an FDA-approved synthetic analog of progesterone, was found to be a powerful neuroprotective antioxidant, preventing light-induced ROS in photoreceptor cells, and subsequent cell death. Norgestrel also prevented light-induced photoreceptor morphological changes that were associated with ROS production, and that are characteristic of RP. Further investigation showed that norgestrel acts via post-translational modulation of the major antioxidant transcription factor Nrf2; bringing about its phosphorylation, subsequent nuclear translocation, and increased levels of its effector protein superoxide dismutase 2 (SOD2). In summary, these results demonstrate significant protection of photoreceptor cells from oxidative stress, and underscore the potential of norgestrel as a therapeutic option for RP.

Abstract Norgestrel (NGT) is a synthetic progestin used in human and veterinary medicine. Adult female mosquitofish were exposed to NGT for 42 d at 377 ng L−1. The fin morphology and the liver transcriptome were assessed. NGT exposure increased ray 4:6 length ratio. As compared to the control, NGT treatment affected the expression of 11,772 annotated transcripts in female mosquitofish. Specifically, we found 5780 were repressed while 5992 were significantly induced. Gene ontology (GO) analysis showed that 53 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways and 158 GO terms were significantly over expressed. Genes showing the largest magnitude of expression changes were related to fin development, androgen biosynthesis, and lipid and fatty acid metabolisms, suggesting the involvement of these biological processes in response to NGT exposure in G. affinis. This first comprehensive study on the transcriptomic alterations by NGT in G. affinis not only provides valuable information on the development of molecular markers but also opens new avenues for studies on the molecular mechanisms of effects of NGT in particular and possibly other progestins in G. affinis. Highlights • Physiological and transcriptomic effects of Norgestrel (NGT) were tested in western mosquitofish (Gambusia affinis). • Results suggested that NGT exposure at environmental concentrations caused masculinization in female mosquitofish. • NGT induced an altered transcription of fin development, androgen biosynthesis, and lipid and fatty acid metabolisms-related genes in the liver. [ABSTRACT FROM AUTHOR]

Synthetic hormones in wastewater effluents released into the aquatic environments may interfere with the normal endocrine systems of fish in receiving streams. Norgestrel (NGT) is a synthetic progestin widely used in oral contraceptives and frequently detected in wastewater effluents. In this study, adult female mosquitofish (Gambusia affinis) were exposed to three environmentally relevant concentrations of norgestrel (NGT) (i.e., 3.6, 35.8, and 368.0 ng L−1) for 42 d, fin morphology, histology of the ovary, and reproductive behaviors were evaluated. The results showed that NGT at all three concentrations caused an increased frequency of atretic follicular cells in ovaries and impaired mating behaviors exhibited by males toward the NGT-exposed females. In mosquitofish exposed to NGT at 35.8 and 368 ng L −1 , the anal fin of females had an increased length ratio of ray4/ray 6, an increased width of ray 3, and increased number of segments in ray 3. The histopathological analysis showed that exposure to NGT increased the incidence of spermatogenesis in ovaries. Mating behavior was impaired 58.4%, 65.7%, and 76.4% ( P <  0.01 in all cases) when mosquitofish were exposed to NGT at 3.6, 35.6 and 368.0 ng L −1 , respectively. The rapid masculinization, the increased frequency of atretic follicles, the incidence of spermatogenesis in the ovary of female fish, and the altered reproductive behaviors suggest that wild populations of mosquitofish could be similarly affected inhabiting in NGT contaminated environments. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the adverse effects of synthetic progestin norgestrel (NGT) on the reproduction of zebrafish by measuring the egg production, histology and transcriptional expression profiles along the hypothalamic-pituitary-gonadal (HPG) axis in adult zebrafish. After a pre-exposure period of 7 days, adult zebrafish were exposed to 6, 29 and 69 ng L −1 NGT for 21 days. The results showed that exposure to 69 ng L −1 NGT led to a significant up-regulation of follicle stimulating hormone, beta polypeptide ( fshb ), luteinizing hormone, beta polypeptide ( lhb ), progesterone receptor ( pgr ), estrogen receptor 1 ( esr1 ) and androgen receptor ( ar ) genes in the brains, as well as significant up-regulation of hydroxysteroid 20-beta dehydrogenase ( hsd20b ) and hydroxysteroid 11-beta dehydrogenase 2 ( hsd11b2 ) genes and down-regulation of 11-beta-hydroxylase ( cyp11b ) gene in the ovaries of females. In the testes of males, an overall down-regulation of steroidogenic acute regulatory protein ( star ), cytochrome P450-mediated side-chain cleavage enzyme ( cyp11a1 ), cyp11b , hsd20b , hydroxysteroid 17-beta dehydrogenase type 3 ( hsd17b3 ), hsd11b2 and ar genes were observed following exposure to different treatments of NGT. These transcriptional alterations imply that NGT could exhibit the potent progestogenic and androgenic activities in zebrafish. Egg production as well as histology in the ovaries and testes was not affected by NGT. Taken together, the overall results demonstrated that NGT could significantly affect transcriptional expression levels of genes related to HPG axis in zebrafish, and whether that change translates to additional physiological effects is needed further research. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the effects of norgestrel (NGT) on gonadal development in adult zebrafish. Adult zebrafish were exposed to NGT for 14 d at 871 ng L−1 for microarray analysis, and a follow-up experiment was conducted to further study the targeted pathway in adult zebrafish after exposure to NGT at 6.7, 83, and 912 ng L−1 by quantitative polymerase chain reaction (qPCR) and histological analysis. The microarray analysis revealed that 11 545 transcripts were identified. Gene ontology analysis showed organ development, system development, multicellular organismal development, single-organism developmental process, and developmental process were significantly enriched. A Venn diagram displayed 434 target genes involved in organ development, and these genes were common in these 5 development-related processes. Kyoto Encyclopedia of Genes and Genomes analysis showed that the notch signaling pathway was the top toxicity pathway, and it was selected as the target pathway for further qPCR analysis. The qPCR analysis revealed significant and dose-dependent alterations of most target genes involved in the notch signaling pathway in the gonads, even at an environmentally relevant concentration of 6.7 ng L−1. The transcriptional patterns were consistent with the notch signaling cascade. In addition, NGT significantly increased the frequency of mature sperm and decreased the frequency of immature sperm at all concentrations. Meanwhile, NGT treatment increased the percentage of mature vitellogenic oocytes and atretic follicles at 912 ng L−1 but decreased the percentage of immature vitellogenic oocytes. Thus, the present study demonstrated significant developmental toxicity in the gonad of adult zebrafish even at environmentally relevant NGT concentrations. Environ Toxicol Chem 2017;36:3267-3276. © 2017 SETAC [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background/aim: This study aimed to compare the levonorgestrel intrauterine system (LNG-IUS) with abdominal hysterectomy (TAH) and total laparoscopic hysterectomy (TLH) as first-line treatments for heavy menstrual bleeding (HMB). Materials and methods: Ninety-eight patients aged 20-55 years who complained of regular heavy menstrual bleeding were enrolled in the study. The TAH group included 29 patients, the LNG-IUS group included 34, and the TLH group included 35. These groups were compared in terms of quality of life and the cost-effectiveness of the selected methods. Quality of life was assessed using the 36-Item Short Form (SF-36), and cost-effectiveness was assessed according to the current cost of each approach. Results: The quality of life parameters, with the exception of mental health, improved significantly in the LNG-IUS, TAH, and TLH groups. The mean costs of the LNG-IUS, TAH, and TLH procedures were $99.15 ± 4.90, $538.82 ± 193.00 and $1617.05 ± 258.44, respectively (P < 0.05). Overall, LNG-IUS was the most cost-effective treatment option. Conclusion: The outcome measures of the SF-36 revealed that after 6 months, these treatments were equal in terms of quality of life, except for mental health. LNG-IUS was the most cost-effective approach. [ABSTRACT FROM AUTHOR]

Synthetic estrogens and progestins are commonly used in human and veterinary medicine. After use, they reach aquatic environments via discharge of wastewaters from human and animals, thus posing potential risks to organisms. So far, very little is known about their combined effects in aquatic organisms. The aim of this study was to investigate the effects of binary mixtures of ethinylestradiol (EE2) and norgestrel (NGT) on embryonic zebrafish ( Danio rerio ) by measuring transcriptional alterations. Zebrafish embryos were exposed to EE2 and NGT alone or in combination at concentrations between 36 and 5513 ng L − 1 for 96 h post-fertilization (hpf). The results showed that most of gene transcriptions of hypothalamic-pituitary-gonadal axis (e.g., Pgr , Mprα , Esr1 , Esr2a , Vtg1 , Ar , Cyp11b , Star , Gnrh3 and Fshb ) and circadian rhythm signaling (e.g., Cry1a , Cry2a , Cry2b , Per3 , Arntl1b , Arntl2 , Clock1a , Cry3 and Cry4 ) displayed most pronounced alterations in the mixtures as compared to single EE2 and NGT exposures. This finding suggests exposure to the binary mixtures of EE2 and NGT produced significantly enhanced effects in fish as compared to single chemical exposures, and their coexistence could have significant environmental implications. [ABSTRACT FROM AUTHOR]

Norplant® is the brand name of the world's first registered subdermal hormonal contraceptive implant, developed by the laboratories of the Population Council, an international organisation working in the area of fertility and population growth. The article revisits the trajectory of this contraceptive in Brazil from its arrival through clinical trials to its eventual ban in 1986 by the Brazilian regulatory agency responsible for approving medications at the time. Its circulation generated controversies related to research practices, side effects and political uses of the drug as a birth control method. This article focuses its analysis on the divergences related to research practices. It uses a controversy analysis technique, reviewing the versions of those involved, investigating their understandings and the effects that this object generated in their networks. Norplant® provoked displacements and associations between civil society groups, State authorities, scientists and physicians, industry, pharmaceutical products, research procedures, bureaucratic instruments, and the female users of the contraceptives. Scientific styles of medical thought were shaken up and new forms of thinking about scientific autonomy began to be discussed in the country. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa ( RP) is a degenerative retinal disease leading to photoreceptor cell loss. In 2011, our group identified the synthetic progesterone 'Norgestrel' as a potential treatment for RP. Subsequent research showed Norgestrel to work through progesterone receptor membrane component 1 ( PGRMC1) activation and upregulation of neuroprotective basic fibroblast growth factor ( bFGF). Using trophic factor deprivation of 661W photoreceptor-like cells, we aimed to further elucidate the mechanism leading to Norgestrel-induced neuroprotection. In the present manuscript, we show by flow cytometry and live-cell immunofluorescence that Norgestrel induces an increase in cytosolic calcium in both healthy and stressed 661Ws over 24 h. Specific PGRMC1 inhibition by AG205 (1 μ m) showed this rise to be PGRMC1-dependent, primarily utilizing calcium from extracellular sources, for blockade of L-type calcium channels by verapamil (50 μ m) prevented a Norgestrel-induced calcium influx in stressed cells. Calcium influx was also shown to be bFGF-dependent, for si RNA knock down of bFGF prevented Norgestrel- PGRMC1 induced changes in cytosolic calcium. Notably, we demonstrate PGRMC1-activation is necessary for Norgestrel-induced bFGF upregulation. We propose that Norgestrel protects through the following pathway: binding to and activating PGRMC1 expressed on the surface of photoreceptor cells, PGRMC1 activation drives bFGF upregulation and subsequent calcium influx. Importantly, raised intracellular calcium is critical to Norgestrel's protective efficacy, for extracellular calcium chelation by EGTA abrogates the protective effects of Norgestrel on stressed 661W cells in vitro. [ABSTRACT FROM AUTHOR]