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Pharmaceutics Apr 2024Long-acting injectable (LAI) formulations provide sustained drug release over an extended period ranging from weeks to several months to improve efficacy, safety, and...
Long-acting injectable (LAI) formulations provide sustained drug release over an extended period ranging from weeks to several months to improve efficacy, safety, and compliance. Nevertheless, many challenges arise in the development and regulatory assessment of LAI drug products due to a limited understanding of the tissue response to injected particles (e.g., inflammation) impacting in vivo performance. Mechanism-based in silico methods may support the understanding of LAI-physiology interactions. The objectives of this study were as follows: (1) to use a mechanistic modeling approach to delineate the in vivo performance of DepoSubQ Provera and formulation variants in preclinical species; (2) to predict human exposure based on the knowledge gained from the animal model. The PBPK model evaluated different elements involved in LAI administration and showed that (1) the effective in vivo particle size is potentially larger than the measured in vitro particle size, which could be due to particle aggregation at the injection site, and (2) local inflammation is a key process at the injection site that results in a transient increase in depot volume. This work highlights how a mechanistic modeling approach can identify critical physiological events and product attributes that may affect the in vivo performance of LAIs.
PubMed: 38675213
DOI: 10.3390/pharmaceutics16040552 -
Scientific Reports Apr 2024Decidualization can be induced by culturing human endometrial stromal cells (ESCs) with several decidualization stimuli, such as cAMP, medroxyprogesterone acetate (MPA)...
Decidualization can be induced by culturing human endometrial stromal cells (ESCs) with several decidualization stimuli, such as cAMP, medroxyprogesterone acetate (MPA) or Estradiol (E). However, it has been unclear how decidualized cells induced by different stimuli are different. We compared transcriptomes and cellular functions of decidualized ESCs induced by different stimuli (MPA, E + MPA, cAMP, and cAMP + MPA). We also investigated which decidualization stimulus induces a closer in vivo decidualization. Differentially expressed genes (DEGs) and altered cellular functions by each decidualization stimuli were identified by RNA-sequence and gene-ontology analysis. DEGs was about two times higher for stimuli that use cAMP (cAMP and cAMP + MPA) than for stimuli that did not use cAMP (MPA and E + MPA). cAMP-using stimuli altered the cellular functions including angiogenesis, inflammation, immune system, and embryo implantation whereas MPA-using stimuli (MPA, E + MPA, and cAMP + MPA) altered the cellular functions associated with insulin signaling. A public single-cell RNA-sequence data of the human endometrium was utilized to analyze in vivo decidualization. The altered cellular functions by in vivo decidualization were close to those observed by cAMP + MPA-induced decidualization. In conclusion, decidualized cells induced by different stimuli have different transcriptome and cellular functions. cAMP + MPA may induce a decidualization most closely to in vivo decidualization.
Topics: Female; Humans; Cells, Cultured; Endometrium; Medroxyprogesterone Acetate; Stromal Cells; Gene Expression; RNA; Decidua
PubMed: 38565619
DOI: 10.1038/s41598-024-58065-z -
BMJ (Clinical Research Ed.) Mar 2024To assess the risk of intracranial meningioma associated with the use of selected progestogens.
OBJECTIVE
To assess the risk of intracranial meningioma associated with the use of selected progestogens.
DESIGN
National case-control study.
SETTING
French National Health Data System (ie, ).
PARTICIPANTS
Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls).
MAIN OUTCOME MEASURES
Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association.
RESULTS
Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use.
CONCLUSIONS
Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.
Topics: Female; Humans; Middle Aged; Progestins; Progesterone; Levonorgestrel; Meningioma; Medroxyprogesterone Acetate; Dydrogesterone; Medrogestone; Promegestone; Case-Control Studies; Meningeal Neoplasms
PubMed: 38537944
DOI: 10.1136/bmj-2023-078078 -
PloS One 2024Observational data suggest lower HIV risk with norethisterone enanthate (NET-EN) than with depo-medroxyprogesterone acetate intramuscular (DMPA-IM) injectable... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of injectable contraception with depot medroxyprogesterone acetate or norethisterone enanthate on estradiol levels and menstrual, psychological and behavioral measures relevant to HIV risk: The WHICH randomized trial.
BACKGROUND
Observational data suggest lower HIV risk with norethisterone enanthate (NET-EN) than with depo-medroxyprogesterone acetate intramuscular (DMPA-IM) injectable contraceptives. If confirmed, a switch between these similar injectable methods would be programmatically feasible and could impact the trajectory of the HIV epidemic. We aimed in this paper to investigate the effects of DMPA-IM and NET-EN on estradiol levels, measures of depression and sexual activity and menstrual effects, relevant to HIV risk; and to ascertain whether these measures are associated with estradiol levels.
METHODS
This open-label trial conducted at two sites in South Africa from 5 November 2018 to 30 November 2019, randomized HIV-negative women aged 18-40 to DMPA-IM 150 mg intramuscular 12-weekly (n = 262) or NET-EN 200 mg intramuscular 8-weekly (n = 259). Data were collected on hormonal, behavioral and menstrual effects at baseline and at 25 weeks (25W).
RESULTS
At 25W, median 17β estradiol levels were substantially lower than at baseline (p<0.001) for both methods: 76.5 pmol/L (interquartile range (IQR) 54.1 to 104.2) in the DMPA-IM group (n = 222), and 69.8 pmol/L (IQR: 55.1 to 89.3) in the NET-EN group (n = 225), with no statistical difference between the two methods (p = 0.450). Compared with DMPA-IM, NET-EN users reported significantly less amenorrhoea, fewer sexual acts, fewer users reporting at least one act of unprotected sex, more condom use with steady partner, more days with urge for sexual intercourse, more days feeling partner does not love her, and more days feeling sad for no reason. We did not find a clear association between estradiol levels and sexual behavior, depression and menstrual effects. Behavioral outcomes suggest less sexual exposure with NET-EN than DMPA-IM. The strength of this evidence is high due to the randomized study design and the consistency of results across the outcomes measured.
CONCLUSIONS
Estradiol levels were reduced to postmenopausal levels by both methods. Secondary outcomes suggesting less sexual exposure with NET-EN are consistent with reported observational evidence of less HIV risk with NET-EN. A randomized trial powered for HIV acquisition is feasible and needed to answer this important question.
TRIAL REGISTRATION
PACTR 202009758229976.
Topics: Humans; Female; Medroxyprogesterone Acetate; Norethindrone; Contraception; Contraceptive Agents, Female; HIV Infections; Estradiol
PubMed: 38530848
DOI: 10.1371/journal.pone.0295764 -
Journal of Public Health in Africa Nov 2023Depot-medroxyprogesterone acetate (DMPA) is a highly effective long acting reversible contraceptive. Alterations in lipid profile have been associated with use of DMPA,...
Depot-medroxyprogesterone acetate (DMPA) is a highly effective long acting reversible contraceptive. Alterations in lipid profile have been associated with use of DMPA, however there is considerable debate about how profound these effects are. Hence the aim of this study is to determine the effect of DMPA on lipid profile and the associated cardiovascular risks. This was a prospective longitudinal study conducted at the family planning clinic of Olabisi Onabanjo University Teaching Hospital Sagamu, Ogun State. Sixty eight new acceptors of DMPA who had their blood samples collected for lipid profile assays at initiation of DMPA, and then at 3 months and 6 months. Data were analyzed using SPSS version 24. After 3 months of DMPA use, there was statistically significant increase in serum Total Cholesterol (TC) concentration (P=0.022), serum Low Density Lipoprotein (LDL) concentration (P=0.033), non significant increase in serum Triglyceride (TG) concentration (P=0.150) and non-significant decrease in serum Higher Density Lipoprotein (HDL) concentration (P=0.076). However, after 6 months of DMPA use, there was statistically significant increase in serum TC concentration (P=0.002), serum LDL concentration (P=0.003), serum TG concentration (P=0.001) and significant decrease in serum HDL concentration (P=0.001). DMPA use is associated with increased serum TC, TG, LDL, and reduction in HDL after 6 months of use. These changes in lipid profile may increase the risk of cardiovascular diseases.
PubMed: 38525248
DOI: 10.4081/jphia.2023.1664 -
Ghana Medical Journal Jun 2023Endometriosis-associated massive haemorrhagic ascites is rare and poses a diagnostic challenge to the gynaecologist due to its resemblance to malignancies, especially...
UNLABELLED
Endometriosis-associated massive haemorrhagic ascites is rare and poses a diagnostic challenge to the gynaecologist due to its resemblance to malignancies, especially ovarian malignancy. We report a 31-year-old nulligravida with progressive abdominal swelling, worsening dysmenorrhea, weight loss and a family history of ovarian tumour. Pelvic ultrasonography and Computed Tomography scans suggested an ovarian mass suspected to be an ovarian malignancy. Exploratory laparotomy revealed massive haemorrhagic ascites (8.6 litre) and multiple nodular masses on the anterior abdominal wall, omentum, bowel and pelvic organs, which were biopsied and confirmed on histopathology to be endometriosis. She had drainage of ascites and hormonal suppression using progestogen (Medroxyprogesterone acetate) with no recurrence in 15 months. Endometriosis should be considered in young, nulligravid women with dysmenorrhea, weight loss and ascites.
FUNDING
None declared.
Topics: Female; Humans; Adult; Ascites; Endometriosis; Dysmenorrhea; Ovarian Neoplasms; Weight Loss
PubMed: 38504753
DOI: 10.4314/gmj.v57i2.12 -
Cureus Feb 2024Low-grade endometrial stromal sarcoma (LGESS) typically has a favorable prognosis. Hormone therapy is considered the first choice of treatment for recurrent LGESS. In...
Low-grade endometrial stromal sarcoma (LGESS) typically has a favorable prognosis. Hormone therapy is considered the first choice of treatment for recurrent LGESS. In this report, we describe a case of recurrent LGESS where hormone therapy was ineffective, chemotherapy showed a partial response (PR), and pazopanib resulted in stable disease (SD). A 50-year-old patient with LGESS underwent a simple total hysterectomy and bilateral adnexectomy (pT1aN0M0, stage IA). Five years later, pelvic tumors and ascites were observed. Exploratory laparoscopy revealed bloody ascites, an 8 cm pelvic tumor, and extensive peritoneal dissemination. Nuclear atypia of the tumor cells was mild, pleomorphism and mitotic figures could not be confirmed, and necrosis was not observed. Immunostaining was positive for CD10 and estrogen receptor, negative for the BCL6 corepressor (BCOR), and showed a low Ki-67 index. Fluorescence in situ hybridization (FISH) examination of the tissue showed rearrangement of the JAZF zinc finger 1 (JAZF1) gene. Multigene panel testing revealed a homozygous deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A). Accordingly, the patient was diagnosed with recurrent LGESS and was treated with an aromatase inhibitor, followed by medroxyprogesterone acetate; both were ineffective. The patient had a PR to chemotherapy (doxorubicin/ifosfamide) and SD to pazopanib. The patient died 1.5 years after recurrence. In conclusion, we present a case of LGESS with a poor prognosis where hormone therapy was ineffective, and chemotherapy and pazopanib were both partially effective. The poor prognosis may have been associated with the CDKN2A homozygous deletion.
PubMed: 38481894
DOI: 10.7759/cureus.54066 -
Frontiers in Endocrinology 2024Historically, progesterone has been studied significantly within the context of reproductive biology. However, there is now an abundance of evidence for its role in... (Review)
Review
Historically, progesterone has been studied significantly within the context of reproductive biology. However, there is now an abundance of evidence for its role in regions of the central nervous system (CNS) associated with such non-reproductive functions that include cognition and affect. Here, we describe mechanisms of progesterone action that support its brain-protective effects, and focus particularly on the role of neurotrophins (such as brain-derived neurotrophic factor, BDNF), the receptors that are critical for their regulation, and the role of certain microRNA in influencing the brain-protective effects of progesterone. In addition, we describe evidence to support the particular importance of glia in mediating the neuroprotective effects of progesterone. Through this review of these mechanisms and our own prior published work, we offer insight into why the effects of a progestin on brain protection may be dependent on the type of progestin (e.g., progesterone versus the synthetic, medroxyprogesterone acetate) used, and age, and as such, we offer insight into the future clinical implication of progesterone treatment for such disorders that include Alzheimer's disease, stroke, and traumatic brain injury.
Topics: Progesterone; Progestins; Neuroprotection; Receptors, Progesterone; Brain
PubMed: 38469139
DOI: 10.3389/fendo.2024.1286066 -
Gynecologic Oncology Reports Apr 2024Progestin therapy is a fertility-sparing treatment option for well-differentiated stage IA endometrioid carcinomas without myometrial invasion. Here, we present a case...
Progestin therapy is a fertility-sparing treatment option for well-differentiated stage IA endometrioid carcinomas without myometrial invasion. Here, we present a case of successful pregnancy and live birth following long-term progestin therapy in a patient with stage II well-differentiated endometrioid carcinoma. A 30-year-old nulliparous woman with an unremarkable medical history presented with abnormal uterine bleeding. A 45 mm mass was identified in the lower uterine segment. An endometrial biopsy revealed grade 1 endometrioid carcinoma, leading to a diagnosis of stage II uterine corpus cancer based on hysteroscopic findings. The patient refused surgical treatment and underwent oocyte retrieval and cryopreservation at another hospital. A subsequent endometrial biopsy revealed a marked reduction in the Ki-67 index from approximately 60 % to less than 10 %, suggesting the possibility of a hormone-sensitive tumor. The patient persistently refused surgery. Therefore, progestin therapy with medroxyprogesterone acetate (MPA) at a dose of 400 mg/day was initiated as a temporary measure until the patient would accept surgery. The tumor gradually reduced in size and eventually disappeared after 9 months. The MPA therapy was discontinued uneventfully after 20 months. Sixteen months after the discontinuation of MPA therapy, atypical endometrial hyperplasia was detected, and a second round of MPA therapy was initiated. Progestin retreatment was successful and was discontinued at 6 months. Four years after the initial treatment, the patient achieved pregnancy through timed intercourse and delivered a healthy baby at 38 weeks of gestation.
PubMed: 38469132
DOI: 10.1016/j.gore.2024.101357 -
BMC Women's Health Mar 2024Robust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of depot medroxyprogesterone acetate, the copper IUD and the levonorgestrel implant on testosterone, sex hormone binding globulin and free testosterone levels: ancillary study of the ECHO randomized clinical trial.
BACKGROUND
Robust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice and development of new methods.
METHODS
In this ancillary study at the East London, South Africa site of the ECHO multicentre randomized trial, we compared effects of three contraceptive methods on serum androgen levels among contraceptive users aged 18 to 35 years. Participants were allocated by centrally-managed randomization to open label depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD) or levonorgestrel implant. The primary outcome was free testosterone at 6 months.
RESULTS
We analysed stored baseline and 6-month serum samples in 398/615 participants (DMPA-IM 131/205, IUD 135/205 and implant 132/205). Median testosterone levels at baseline were DMPA-IM 0.82, IUD 0.9 and implant 0.87 nmol/L; at 6 months, DMPA 0.68 (lower than IUD, mean percentage difference 28.35, (p < 0.001), IUD 0.86 (unchanged) and implant 0.66, lower than IUD, mean percentage difference - 22.98, p < 0.001). Median SHBG levels at baseline were DMPA 52.4, IUD 50.5 and implant 55.75 nmol/L; at 6 months, DMPA 40.65, lower than IUD (mean percentage difference 21.19, p = 0.005), IUD 49.1 (unchanged), and implant 23.35 nmol/L, lower than IUD (mean percentage difference - 50.04, p < 0.001 and than DMPA (mean percentage difference - 39.45, p < 0.001). Free testosterone levels at baseline were DMPA 10, IUD 12 and implant 11 pmol/L; at 6 months, DMPA 11, less than IUD (mean percentage difference 13.53, p = 0.047), IUD 12 and implant 14, higher than IUD (mean percentage difference 14.15, p = 0.038) and than DMPA, (mean percentage difference 29.60, p < 0.001).
CONCLUSIONS
This is the first randomized trial to show lower SHBG and higher free testosterone with the levonorgestrel implant than with DMPA, and contrasts with reports of increased SHBG with combined oral ethinyl estradiol/levonorgestrel use, and reduced androgens (and impaired sexual function) reported with the etonorgestrel implant. The higher free testosterone with the LNG implant might improve sexual function, mood and bone health as well as increasing side-effects such as acne and hirsutism, and is consistent with the greater sexual activity (with respect to multiple sex partners, new sex partner and unprotected sex) with the implant compared with DMPA documented in the ECHO study.
ECHO TRIAL REGISTRATION
ClinicalTrials.gov , number NCT02550067 15/09/2015. Contraception, or family planning, is central to the role of women in societies. It is most important to have accurate information on the relative side-effects of various contraceptive options in order to empower women to make informed choices regarding their preferred method. Hormonal contraceptives contain various forms of the female sex hormones, estrogens and/or progestogens. These hormones have direct effects on the users, as well as modifying the levels of the users' own circulating sex hormones, both the 'female' and the 'male' sex hormones (androgens). In this study, consenting participants requesting contraception, were allocated randomly to receive either depot medroxyprogesterone acetate (DMPA-IM) a 3-monthly progestogen injection, the copper intrauterine device (IUD), a non-hormonal contraceptive inserted within the womb, or the levonorgestrel implant, a device placed under the skin which releases a progestogen for 5 years. We measured the participants' androgen levels after 6 months, and found for the first time that the active form of testosterone (free testosterone) was 29% higher with the implant than with DMPA-IM. The level with the IUD was intermediate, and significantly different from the other two methods. This finding is relevant to the effects experienced by users of these methods, because free testosterone has effects on sexual function, bone health and mood, as well as on conditions such as acne and hair distribution patterns.
Topics: Female; Humans; Acne Vulgaris; Androgens; Contraceptive Agents, Female; Intrauterine Devices, Copper; Levonorgestrel; Medroxyprogesterone Acetate; Progestins; Sex Hormone-Binding Globulin; Testosterone; Adolescent; Young Adult; Adult
PubMed: 38459552
DOI: 10.1186/s12905-024-02990-8