New Contraception Update — Annovera, Phexxi, Slynd, and Twirla

Purpose of Review In this review, we discuss the efficacy, safety, and benefits of four new contraceptive products available in the USA, specifically Annovera, Phexxi, Slynd, and Twirla. Recent Findings Annovera is a vaginal ring releasing ethinyl estradiol and segesterone acetate that can be used for up to one year (13 cycles), offering patients an effective, user-controlled option that may improve contraceptive access for those in low-resource settings or those with barriers to retrieving monthly prescriptions; however, given limited efficacy and safety data in people with body mass index (BMI) > 29 kg/m2, clinicians may consider whether Annovera is an appropriate contraceptive method for obese patients if there are other acceptable alternatives. Phexxi prescription-only vaginal gel is a user-controlled, non-hormonal, on-demand contraceptive method that represents a novel addition to the market with its additional uses as a personal lubricant and as a potential microbicide for urogenital infection prevention. Slynd, a drospirenone-only pill, provides more flexibility for delayed or missed pills while maintaining efficacy and a more favorable bleeding profile compared with previously available progestin-only pills. Lastly, Twirla is a transdermal patch releasing ethinyl estradiol and levonorgestrel that offers users an additional option for a user-controlled, combined hormonal contraceptive method without daily dosing; however, prescription is limited to patients with BMI < 30 kg/m2 due to decreased efficacy and VTE events in people with obesity. Summary The addition of these products expands the available options for pregnancy prevention to address unmet contraceptive needs.

Observational Study for Adverse Effects and Discontinuation with Long-Term Post-Operative Hormonal Treatment for Endometriosis in Real-World Practice

Objectives: To evaluate the side effects and causes of discontinuation of either combined oral contraceptives or dienogest (DNG) used to prevent recurrence in patients with surgically confirmed endometriosis.Methods: We retrospectively analyzed the medical records of 213 women with endometriosis who had been treated with combined oral contraceptives (ethinyl estradiol 0.02 mg/drospirenone 3 mg [EE/DRSP]) or DNG 2 mg for 12 months or more. The side effects reported by the patients, laboratory parameters, causes of discontinuation of medication, and recurrence rates were evaluated one, two, three, four, and five years after starting medication (Y1, Y2, Y3, Y4, and Y5).Results: EE/DRSP were administered to 59 patients, while DNG was administered to 154 patients. The mean durations of postoperative use of EE/DRSP and DNG were 44.5 ± 22.6 months and 23.6 ± 13.5 months, respectively. The prevalence of side effects was 27.1%, 19.0%, 10.0%, 10.5%, and 7.4% in the EE/DRSP group and 29.2%, 15.7%, 14.0%, 23.1%, and 0.0% in the DNG group at Y1, Y2, Y3, Y4, and Y5, respectively. The discontinuation rates were 1.7%, 1.7%, 4.0%, 0.0%, and 7.4% at Y1, Y2, Y3, Y4, and Y5, respectively, in the EE/DRSP group and 10.4%, 3.3%, 4.0%, 3.8%, and 0.0% at the same times in the DNG group. The recurrence rates were less than 4% in both the groups.Conclusions: The side effects of commonly prescribed postoperative hormone treatments were relatively mild, and the occurrence of side effects decreased with continuous administration. Further, the long-term use of postoperative hormone treatments is likely to prevent recurrence of endometriosis after surgery.

The results of immunohistochemical study of signaling pathways’ markers of proliferation in uterine leiomyoma in women using hormonal contraception.

Objective. To elucidate the influence of various components of hormonal contraception in women with uterine leiomyoma (UL) on the key molecular and cellular mechanisms of its proliferation. Methods. Antigen Ki-67, estrogen receptors (ER) and progesterone receptors (PR) were determined by immunohistochemical methods in 230 samples of UL preparations obtained during myomectomy. Depending on the composition of the components of hormonal contraceptives that women used for 12 months before the operation, 8 study groups were created: Group I - control, without the use of any hormonal contraception; Group II - the use of COCs containing 20 μg of ethinylestradiol and 0.075 mg of gestaden; Group III - COCs (30 μg ethinylestradiol and 0.075 mg gestaden) Group IV - COCs (30 μg ethinylestradiol and 0.15 mg desogestrel) Group V - COCs (30 μg ethinyl estradiol and 0.15 mg levonorgestrel) Group VI - COCs (30 μg ethinyl estradiol and 2 mg dienogest) Group VII - COCs (30 μg ethinylestradiol and 3 mg drospirenone) Group VIII - (intrauterine levonorgestrel releasing system (IUD-LNG). Results. In UL samples from group I, an increase of Ki-67 positive cells in 3.4 times was observed (3.1 ± 0.03%; p <0.04) in comparison with intact myometrium (IM) (0.9 ± 0.06%), which is evidence of a higher cell proliferation in the UL, a 3.1-fold increase in the H-index of ER expression - 39.4 ± 4.3 (p <0.05) versus 12.9 ± 1.6 in the group with IM I and in 2.6 times of PR expression - 21.1 ± 1.7 (p <0.05) compared to IM - 8.2 ± 1.4, which may indicate a greater sensitivity of UL to sex hormones and their promoter role in UL proliferation. Expression of Ki-67 in UL samples in women taking COCs, which included dienogest (1.8 ± 0.03%, p <0.05) - group VI and desogestrel (1.9 ± 0.03%, p <0.05) - group IV, was, 42.0% and 38.8% respectively, what ois less than in group I UL, which can be regarded as the cytoprotective effect of the progestogen component of COC on the mitotic activity of UL cells. A positive trend in the expression of Ki-67 persisted when women used COCs containing gestodene (2.1 ± 0.02%; p <0.05) - group III and levonorgestrel (2.2 ± 0.04%, p <0.05) - group V, in which the expression of Ki-67 was shown by a smaller number of PM cells, respectively, by 32.3% and 25.8% than in group I PM, and also to a lesser extent - in group VIII (COC with droperidone), where the mean value of Ki-67 expression in LM samples was 2.6 ± 0.02% and was 16.9% less than in LM group I. An increase in the dose of ethinyl estradiol in COCs from 20 μg (group II) to 30 μg (group III) did not significantly affect the expression of Ki-67, therefore, the content of estrogens in modern low-dose COCs does not contribute to an increase in proliferation in the LM, and the non-contraceptive antiproliferative effect is associated exclusively with biological and the pharmacological properties of individual gestagens in the composition of COCs. It was proved that the studied COCs did not significantly affect the expression of ER and PGR. There was no significant difference in the expression of the Ki-67 marker (2.9 ± 0.04%, p <0.05) in UL cells in women using LNG-IUD for contraception, compared with group I. Conclusion. The results of the study have shown that when choosing a drug for hormonal contraception in women with UL, preference should be given to combined hormonal drugs that contain progestogens with the most pronounced antiproliferative properties (dienogest, desogestrel and levonorgestrel).

The Uptake of Ethinyl-Estradiol and Cortisol From Water by Mussels (Mytilus spp.)

Previous toxicokinetic studies have shown that mussels (Mytilus spp.) can readily absorb the three main mammalian sex steroids, estradiol (E2), testosterone (T) and progesterone (P) from water. They also have a strong ability to store E2 and the 5α-reduced metabolites of T and P in the form of fatty acid esters. These esters were shown to have half-lives that were measured in weeks (i.e. they were not subject to fast depuration). The present study looked at the toxicokinetic profile of two other common steroids that are found in water, the potent synthetic oestrogen, (ethinyl-estradiol) (EE2; one of the two components of ‘the pill’), and cortisol, a natural stress steroid in vertebrates. In the first three hours of uptake, tritiated EE2 was found to be taken up at a similar rate to tritiated E2. However, the levels in the water plateaued sooner than E2. The ability of the animals to both esterify and sulphate EE2 was found to be much lower than E2, but nevertheless did still take place. After 24 h of exposure, the majority of radiolabelled EE2 in the animals was present in the form of free steroid, contrary to E2, which was esterified. This metabolism was reflected in a much lower half-life (of only 15 h for EE2 in the mussels as opposed to 8 days for E2 and &gt;10 days for T and P). Intriguingly, hardly any cortisol (in fact none at all in one of the experiments) was absorbed by the mussels. The implications of this finding in both toxicokinetic profiling and evolutionary significance (why cortisol might have evolved as a stress steroid in bony fishes) are discussed.

Combined Intranasal Insulin/Saxagliptin/Metformin Therapies Ameliorate the Effect of Combined Oral Contraceptive- (COC-) Induced Metabolic Syndrome (MetS) with a Major Target on Glucose Metabolism in Adult Female Wistar Rats

Objective. To evaluate the effect of the chronic use of combined oral contraceptives (COCs: ethinyl estradiol and levonorgestrel) on the indices of metabolic syndrome in adult female Wistar rats and possible therapeutic management. Materials and Methods. 64 female Wistar rats received either distilled water, norethindrone (NOR), COC, intranasal insulin (INI), metformin (MET), saxagliptin (SAX), INI+MET, and INI+SAX. After 8 weeks of exposure to COC, the animals were sorted into the therapeutic groups. Several parameters were assayed for, such as body weight changes, fasting blood glucose (FBG) level, insulin levels, inflammatory cytokines, and glycated hemoglobin (Hb1Ac). Results. The levels of FBG, insulin, and Hb1Ac were increased consequent upon COC treatment. Treatment with INI+SAX and INI+MET reduced significantly the levels of FBG and Hb1Ac; in addition, the level of insulin was significantly increased in the INI+MET groups ( p ≤ 0.05 ). Serum lipid profile analysis showed a statistical reduction in high-density lipoprotein (HDL) level; this reduction was also significantly reversed in the INI+SAX group. Reduced catalase activity observed in the COC group was reversed in the INI+MET group ( p ≤ 0.05 ). A nonsignificant increase in the level of TNF-α as a result of COC treatment was reversed by INI and INI+MET treatment. Liver GLUT4 and G-6-phosphate levels were significantly increased by COC treatment, and this effect was reversed by INI+SAX in both assays, respectively ( p ≤ 0.01 ). Conclusions. The use of MET and SAX in combination with INI has been shown to reverse some indices of MetS. This study proposes a clinical phase to backup and ascertain these preclinical findings.

17α-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial

Background Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS. Methods All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation). Results A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood–brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration. Conclusions EE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.