Molecular Assessment of Proadipogenic Effects for Common-Use Contraceptives and Their Mixtures.

Hormonal contraceptives are widely prescribed due to their effectiveness and convenience and have become an integral part of family planning strategies worldwide. In the United States, approximately 65% of reproductive-aged women are estimated to be using contraceptive options, with approximately 33% using one or a combination of hormonal contraceptives. While these methods have undeniably contributed to improved reproductive health, recent studies have raised concerns regarding their potential effect on metabolic health. Despite widespread anecdotal reports, epidemiological research has been mixed as to whether hormonal contraceptives contribute to metabolic health effects. As such, the goals of this study were to assess the adipogenic activity of common hormonal contraceptive chemicals and their mixtures. Five different models of adipogenesis were used to provide a rigorous assessment of metabolism-disrupting effects. Interestingly, every individual contraceptive (both estrogens and progestins) and each mixture promoted significant adipogenesis (eg, triglyceride accumulation and/or preadipocyte proliferation). These effects appeared to be mediated in part through estrogen receptor signaling, particularly for the contraceptive mixtures, as cotreatment with fulvestrant acted to inhibit contraceptive-mediated proadipogenic effects on triglyceride accumulation. In conclusion, this research provides valuable insights into the complex interactions between hormonal contraceptives and adipocyte development. The results suggest that both progestins and estrogens within these contraceptives can influence adipogenesis, and the specific effects may vary based on the receptor disruption profiles. Further research is warranted to establish translation of these findings to in vivo models and to further assess causal mechanisms underlying these effects.

Insights into the Behavior of Triple-Negative MDA-MB-231 Breast Carcinoma Cells Following the Treatment with 17ß-Ethinylestradiol and Levonorgestrel.

Oral contraceptives (OCs) are widely used due to their efficiency in preventing unplanned pregnancies and treating several human illnesses. Despite their medical value, the toxicity of OCs remains a public concern. Previous studies indicate the carcinogenic potential of synthetic sex hormones and their link to the development and progression of hormone-dependent malignancies such as breast cancer. However, little is known about their influence on the evolution of triple-negative breast carcinoma (TNBC), a malignancy defined by the absence of estrogen, progesterone, and HER2 receptors. This study reveals that the active ingredients of modern OCs, 17ß-Ethinylestradiol, Levonorgestrel, and their combination induce differential effects in MDA-MB-231 TNBC cells. The most relevant behavioral changes occurred after the 24 h treatment with 17ß-Ethinylestradiol, summarized as follows: (i) decreased cell viability (64.32% at 10 µM); (ii) cell roundness and loss of confluence; (iii) apoptotic aspect of cell nuclei (fragmentation, membrane blebbing); and (iv) inhibited cell migration, suggesting a potential anticancer effect. Conversely, Levonorgestrel was generally associated with a proliferative activity. The association of the two OCs exerted similar effects as 17ß-Ethinylestradiol but was less effective. Further studies are necessary to elucidate the hormones' cytotoxic mechanism of action on TNBC cells.

Estradiol-Responsive miR-365a-3p Interacts with Tissue Factor 3'UTR to Modulate Tissue Factor-Initiated Thrombin Generation.

BACKGROUND: High estradiol (E2) levels are linked to an increased risk of venous thromboembolism; however, the underlying molecular mechanism(s) remain poorly understood. We previously identified an E2-responsive microRNA (miR), miR-494-3p, that downregulates protein S expression, and posited additional coagulation factors, such as tissue factor, may be regulated in a similar manner via miRs. OBJECTIVES: To evaluate the coagulation capacity of cohorts with high physiological E2, and to further characterize novel E2-responsive miR and miR regulation on tissue factor in E2-related hypercoagulability. METHODS: Ceveron Alpha thrombin generation assay (TGA) was used to assess plasma coagulation profile of three cohorts. The effect of physiological levels of E2, 10 nM, on miR expression in HuH-7 cells was compared using NanoString nCounter and validated with independent assays. The effect of tissue factor-interacting miR was confirmed by dual-luciferase reporter assays, immunoblotting, flow cytometry, biochemistry assays, and TGA. RESULTS: Plasma samples from pregnant women and women on the contraceptive pill were confirmed to be hypercoagulable (compared with sex-matched controls). At equivalent and high physiological levels of E2, miR-365a-3p displayed concordant E2 downregulation in two independent miR quantification platforms, and tissue factor protein was upregulated by E2 treatment. Direct interaction between miR-365a-3p and F3-3'UTR was confirmed and overexpression of miR-365a-3p led to a decrease of (1) tissue factor mRNA transcripts, (2) protein levels, (3) activity, and (4) tissue factor-initiated thrombin generation. CONCLUSION: miR-365a-3p is a novel tissue factor regulator. High E2 concentrations induce a hypercoagulable state via a miR network specific for coagulation factors.

The Impact of Ethinyl Estradiol on Metformin Action on Prolactin Levels in Women with Hyperprolactinemia.

BACKGROUND: Metformin reduced prolactin levels only in women with hyperprolactinemia. OBJECTIVE: The purpose of this case-control study was to compare metformin action on lactoctrope function between women receiving oral contraceptive pills and women not using hormonal contraception. METHODS: The study included two groups of matched women with elevated prolactin levels and new-onset prediabetes or diabetes. The first group consisted of 20 women using oral contraceptive pills for at least 12 months before entering the study, while the second group included 20 patients not using any hormonal contraception. Over the whole study period, all women were treated with metformin (1.7-3 g daily). Circulating levels of glucose, insulin, prolactin, thyrotropin, free thyroid hormones, adrenocorticotropic hormone, gonadotropins and insulin-like growth factor-1 were measured at the beginning and at the end of the study (16 weeks later). RESULTS: Thirty-eight patients completed the study. Metformin reduced plasma glucose levels and improved insulin sensitivity but the latter effect was stronger in women receiving oral contraceptive pills than in women not using any contraception. Although metformin treatment decreased plasma prolactin levels in both study groups, this effect was stronger in women taking oral contraceptive pills. Only in this group of women, metformin increased plasma luteinizing hormone levels. The changes in plasma prolactin correlated with their baseline insulin sensitivity and the effect of metformin on insulin sensitivity. Metformin did not affect plasma levels of thyrotropin, free thyroxine, free triiodothyronine, follicle-stimulating hormone, adrenocorticotropic hormone and insulin-like growth factor-1. CONCLUSIONS: The obtained results suggest that the effect of metformin on overactive lactotropes depends on estrogen levels.

Simultaneous nicotine and oral contraceptive exposure alters brain energy metabolism and exacerbates ischemic stroke injury in female rats.

Smoking-derived nicotine (N) and oral contraceptives (OC) synergistically exacerbate ischemic brain damage in the females and underlying mechanisms remain elusive. Our published study showed that N toxicity is exacerbated by OC via altered mitochondrial function owing to a defect in the activity of cytochrome c oxidase. Here, we investigated the global metabolomic profile of brains of adolescent female Sprague-Dawley rats exposed to N ± OC. Rats were randomly exposed to saline or N + /-OC for 16-21 days followed by random allocation into two cohorts. One cohort underwent transient middle cerebral artery occlusion and histopathology was performed 30 days later. From the second cohort, cortical tissues were collected for an unbiased global metabolomic profile. Pathway enrichment analysis showed significant decrease in glucose, glucose 6-phosphate and fructose-6-phosphate, along with a significant increase in pyruvate in the N + /-OC exposed groups when compared to saline (p < 0.05), suggesting alterations in the glycolytic pathway which were confirmed by Western blot analyses of glycolytic enzymes. Infarct volume quantification showed a significant increase following N alone or N + OC as compared to saline control. Because glucose metabolism is critical for brain physiology, altered glycolysis deteriorates neural function, thus exacerbating ischemic brain damage.

Luteotropic effects of human chorionic gonadotropin administered 7.5 days after synchronous estrous induction in Morada Nova ewes.

This study was conducted in ewes to assess effects of human chorionic gonadotropin (hCG) administration after imposing an estrous induction treatment regimen. Ewes (n = 115) were treated with a 60 mg medroxyprogesterone-intravaginal-sponge for 6 d plus 200 IU of equine chorionic gonadotropin (eCG) im and 37.5 µg d-cloprostenol im 36 h before sponge removal (Day 0). After natural mating, ewes having at least one corpus luteum (CL; n = 108) were administered either 1 mL of saline (G-Control; n = 53) or 300 IU of hCG (G-hCG; n = 55) on Day 7.5 after sponge removal (Day 0). Ovarian ultrasonography and blood collection were performed on Days 7.5, 13.5, 17.5, 21.5, and 30.5. Accessory CL (aCL) were observed in 81.5 % (G-hCG) and 0.0 % (G-Control) of ewes (P = 0.0001). Diameter, area, and volume of luteal tissue were greater (P < 0.05) in G-hCG from Day 13.5 to 30.5. Progesterone (P4) concentrations were greater (P < 0.05) on Days 13.5, 17.5, 21.5 and 30.5 for ewes of the G-hCG group. Pregnancy percentage was similar (P = 0.25) between groups [47.1 % (G-control) compared with 60.0 % (G-hCG)], although total number of lambs produced by estrous synchronized ewes was greater (P = 0.005) in ewes of the G-hCG group (90.9 % compared with 66.0 %). In conclusion, hCG administration 7.5 days after sponge removal from Morada Nova ewes during the non-breeding season is an effective treatment to induce aCL formation, improve luteal tissue biometry and P4 concentrations, and to enhance the total number of lambs born.

Effects of progestin-only contraceptives on the endometrium.

INTRODUCTION: The contraceptive activity of synthetic progestins is mediated through three basic mechanisms: (a) An anti-gonadotrophic action leading to the inhibition of ovulation; (b) Changes in cervical mucus characteristics that inhibit sperm penetration and (c) desynchronization of the endometrial picture necessary for implantation. AREAS COVERED: Mechanisms involved in the progestin-induced endometrium desynchronization are individually reviewed for each of the routes of administration and, whenever possible, by individual members of the various families of synthetic progestin derivatives. EXPERT OPINION: For contraceptive purposes, progestins are today administered through several routes: orally, as injections, subdermally and via the vagina or the uterine cavity. Given this variety of modalities, their effects may differ, depending on the route of administration, concentration reached at the level of the endometrium and the duration of use. These are characterized by inactivation of the endometrium. Progestin-only contraception provides a safe and effective control of fertility regulation, although, they are associated with the problem of endometrial break through bleeding that may lead to discontinuation. Unfortunately, in spite of a major research effort over two decades, there is not, as yet, an established long-term intervention available to manage bleeding irregularities, making mandatory a deeper understanding of the mechanisms involved is required.

Comparison of effect of preoperative dienogest and gonadotropin-releasing hormone agonist administration on laparoscopic cystectomy for ovarian endometriomas.

PURPOSE: To compare the effects of preoperative dienogest (DNG) and gonadotropin-releasing hormone (GnRH) agonist administration on the improvement of preoperative symptoms and surgical outcomes in patients who underwent laparoscopic cystectomy for ovarian endometriomas. METHODS: Seventy patients who were scheduled for laparoscopic surgery were enrolled in the study. They were divided into two groups: 35 patients who received DNG for 4 months preoperatively (group D) and 35 patients who received low-dose sustained-release goserelin acetate for 4 months preoperatively (group G). Preoperative outcomes, including pain score associated with endometriosis, using the numerical rating scale (NRS), adverse events of hormonal therapy and Kupperman index (KI) before and after treatment, surgical outcomes including total surgical duration and blood loss, and postoperative recurrence of endometrioma were compared between the two groups. RESULTS: Regarding preoperative symptoms, NRS and KI at 4 months after preoperative hormonal therapy were significantly lower in group D than in group G (NRS, 5.3 ± 5.5 vs. 2.7 ± 3.9; P = 0.01; KI, 16.0 ± 11.0 vs. 9.2 ± 7.6; P = 0.006). Regarding adverse events, the incidence of hot flashes was significantly lower in group D than in group G (P < 0.001). Meanwhile, the incidence of breast pain and metrorrhagia was significantly higher in group D than in group G (P = 0.04 and P < 0.001, respectively). The total surgical duration and blood loss were not significantly different between the groups. At 12 months after surgery, ovarian endometrioma did not recur in either group. CONCLUSION: Preoperative administration of DNG is more valuable for patients with endometriosis and scheduled for laparoscopic surgery to improve symptoms with good efficacy and tolerability than the administration of GnRH agonist.

A progestin isn't a progestin: dienogest for endometriosis as a blueprint for future research - Review as a contribution for discussion.

The different etiopathogenetic mechanisms and the diversity of clinical features of endometriosis has not yet allowed to identify a causal pharmacological monotherapy satisfying the unresolved medical needs in this important female disease. Therefore, despite the search for new therapeutic principles for the indication, the strategy of gradual optimization of established therapeutic principles should not be disregarded.In the case of progestins, the fact that each compound has its own, specific profile may allow to study the therapeutic relevance of the various signal cascades influenced by their receptors.Using the example of the progestin dienogest, the different genomic and non-genomic mechanisms of action are discussed. It is pharmacodynamic profile is unique compared to other progestins.In light of the emerging multitude of pathomechanisms in endometriosis, a monotherapy may not be possible, and then the search for broad spectrum compounds or combination therapies with dual or multiple mode of action in a clinically relevant dose range might be considered. The progestogenic action may greatly benefit from, by way of example, additional anti-inflammatory and/or anti-fibrotic and/or pro-apoptotic activities. Such a strategy could lead to new drug classes.

Influence of sex, menstrual cycle, and hormonal contraceptives on egocentric navigation with or without landmarks.

This study examines the influence of sex, menstrual cycle, hormonal contraceptives (HC) and sex hormone levels in following egocentric navigation instructions with or without landmarks. Estradiol seem to bias the reference frame for navigation during estrous cycle of female rats. However, previous studies in humans found no differences in overall navigation between women in their early follicular and mid-luteal menstrual cycle phases, whose performance was worse than that of men. Our study hypothesis was that the performance of women would be improved during the peri-ovulatory phase and would remain the same during placebo and active phases of HC users. The study included 21 men, 62 women with natural menstrual cycle (21 during early follicular phase, 20 during peri-ovulatory phase, and 21 during mid-luteal phase), and 38 women that were receiving HC (13 during placebo phase and 25 during active phase). The men outperformed the women with a natural menstrual cycle when following egocentric instructions without landmarks. However, the women's performance varied according to the phase of their menstrual cycle, differing from men during early follicular and mid-luteal phases but not during the peri-ovulatory phase. The use of HC also improved the performance of women to the extent that the difference with men disappeared. No differences were observed between HC-placebo and HC-active user groups during egocentric navigation without landmarks and among all groups during egocentric navigation with landmarks. Analysis of salivary hormones showed that testosterone levels were higher in men and that estradiol levels in women were higher during peri-ovulatory and mid-luteal phases and also in HC users. Progesterone levels were higher in women during the mid-luteal phase. These results appear compatible with beneficial effect of testosterone and estradiol on egocentric navigation without landmarks and with a block of this effect produced by progesterone.

Drospirenone 4 mg-only pill (DOP) in 24+4 regimen: a new option for oral contraception.

INTRODUCTION: The use of progestin-only pills (POPs) is still relatively infrequent, mainly for their unpredictable effect on menstrual bleeding. A new POP consisting of 4 mg drospirenone (DRSP) for 24 days plus 4-day hormone-free interval has been developed to address this need. DRSP is a potent progestin analogue of spironolactone, with antiandrogenic and antimineralocorticoid properties. AREAS COVERED: This is a narrative review of the available data on the pharmacotherapy of the new DRSP-only pill. The research includes aspects of pharmacokinetics/pharmacodynamics of the compound: the main focus is on the clinical effects of DRSP-only pill in terms of contraceptive efficacy, haemostatic effect, safety, tolerability and bleeding patterns. EXPERT OPINION: The DRSP-only pill presents a similar Pearl Index to that of common combined hormonal contraceptives: it is a POP with a better bleeding profile than traditional POPs (higher rates of scheduled bleedings and much lower rates of unscheduled intracyclic bleeding/spotting) which could increase its acceptability and the panorama of possible users. For these reasons, DRSP-only pill represents a real step forward in oral contraception with only progestins, even if the bleeding patterns during its use are still different to oestrogen-containing products (i.e. lower rates of scheduled bleedings and higher rate of amenorrhea).

Oral contraceptives increase platelet microparticle levels in normal-weight women with polycystic ovary syndrome.

PURPOSE: Platelet microparticles (PMPs), which are microvesicles shed from platelets, participate in inflammation, vascular homeostasis, and thrombosis. PMPs are increased in obese women with polycystic ovary syndrome (PCOS). Agents that modulate hormonal aspects of PCOS could affect the levels of PMPs. The aim of the present study was to evaluate the effects of oral contraceptives (OCPs), antiandrogen, and metformin use for 6 and 12 months on PMPs in normal-weight women with PCOS. METHODS: Forty-five women with PCOS and 13 healthy women were recruited. Biochemical, hormonal, and clinical parameters were recorded. Women with PCOS received treatment with OCPs, OCPs+antiandrogens, or metformin, depending on their main complaint or clinical/biochemical findings. PMPs were measured at baseline and after 6 and 12 months. RESULTS: At baseline, patients with PCOS had higher levels of PMPs than controls (p = 0.017), which increased after 6-month treatment with OCPs (p = 0.006). Subsequently, they decreased after 12-month treatment (p = 0.046). Metformin had no effect on PMP levels. CONCLUSION: In conclusion, PMP levels are increased in PCOS and further increase with OCP use. This effect could possibly contribute to the increased risk of venous thromboembolism associated with OCP use. However, further studies are needed to elucidate the exact role of PMPs in PCOS.

Exogenous progestogen does not affect first-wave follicle populations and oocyte quality during ovarian stimulation with FSH in sheep.

The effect of short-term administration of medroxyprogesterone acetate (MPA) or natural progesterone (P4) during ovarian stimulation with FSH on oocyte recovery was investigated in Santa Inês ewes. Ewes were treated with an intravaginal sponge containing MPA for 6 d; GnRH was applied 36 h after sponge removal and FSH was given in 3 injections (40, 24, and 16 mg, respectively) every 12 h after (D0, approximate ovulation time). At the first FSH dose, the ewes received either a new MPA sponge (n = 10) or a controlled device for internal release impregnated with P4 (n = 10) or did not receive any device (n = 10). Ovarian dynamics were assessed every 12 h by transrectal ultrasonography from D-3 to D2. Oocytes were recovered by laparoscopic ovum pick-up (LOPU) on D2 and graded by morphologic quality. The number of small, medium, and large follicles at D0 and D2 (ultrasound examinations), number of both follicles aspirated and oocytes recovered at LOPU, recovery rate, and oocyte grade did not differ (P > 0.05) among treatments. Thus, the short-term use of MPA or P4 during ovarian stimulation did not affect the first-wave follicle population or morphologic quality of oocytes. We would suggest that, in this protocol, the use of exogenous progestin is unnecessary.

Variations in sleep associated with different types of hormonal contraceptives.

Progesterone and some of its metabolites are neuroactive steroids that affect sleep by increasing melatonin secretion and stimulating GABA-A receptors. The effect of progestogens in hormonal contraceptives on sleep has not been thoroughly investigated. This observational study assessed possible associations in sleep changes induced by estrogen-progestogens in contraceptives in 108 women between the ages of 20 and 50 years. We assessed mean nightly sleep time with a 31-day sleep diary, and subjective sleep quality with the five subjective subscores of the Pittsburgh Sleep Quality Index (PSQI). Included women were of childbearing age, healthy, sexually active and had been using a hormonal contraceptive method (pill, intrauterine system (IUS), subcutaneous implant, vaginal ring) for at least six months. Results were compared to a matched control group that did not use hormonal contraceptives. The longest mean nightly sleep time, compared to control (450 min), occurred in women who used progestogen-only oral contraception (510 min), followed by IUS delivery of levonorgestrel 13.5 mg (480 min) and oral ethinylestradiol 0.02/0.03 mg plus gestodene 0.075 mg (475 min). Global subjective sleep quality was influenced most by the administration of etonorgestrel 0.120 mg/ethinylestradiol 0.015 mg via the vaginal route. Our results show that low-doses of progestins affect various aspects of sleep, and that this is influenced by the route of administration.

Natural history of ovarian high-grade serous carcinoma from time effects of ovulation inhibition and progesterone clearance of p53-defective lesions.

High-grade serous carcinoma is the most common and devastating type of ovarian cancer; its etiology, mechanism of malignant transformation, and origin remain controversial. Recent studies have identified secretory cells at the fimbria of the fallopian tube as the cell-of-origin of high-grade serous carcinoma, acquiring TP53 mutation, evolving to tubal precursor lesions, including "p53 signature" and serous tubal intraepithelial carcinoma, and metastasizing to the ovary as clinically evident ovarian cancer. The etiological mechanisms associated with known epidemiological risk factors, i.e., ovulation and retrograde menstruation, have also been suggested. Mutagens and transforming growth factors, such as reactive oxygen species and insulin-like growth factor axis proteins, as well as the apoptosis-rescuing protein hemoglobin are abundantly present in the ovulatory follicular fluid and peritoneum fluid, which bathes the fimbrial epithelium, and induces malignant transformation after repeated exposure. In accordance with the proposed cleansing effect of progesterone from studies on oral contraceptive use or term pregnancy, a recent study indicated that the p53-null tubal epithelial cells are selectively cleared by progesterone depending on its progesterone receptor. In this report, by analyzing different time effects of oral contraceptive use or pregnancy in the prevention of ovarian cancer and by aligning them with the carcinogenic and cleansing clearance concepts of ovulation and progesterone, as well as the fact of progressive loss of progesterone receptor during tubal transformation, we deduced the natural history of ovarian high-grade serous carcinoma. The natural history begins at the first ovulation and spans for more than 30 years, taking 10 years from the normal tubal epithelium to the "p53 signature" status, another 15 years to progesterone receptor negative serous tubal intraepithelial carcinoma, and a final 5+ years to high-grade serous carcinoma. The estimated natural history may help understand the pathogenesis of high-grade serous carcinoma and defines the window for early detection and chemoprevention.

No evidence that hormonal contraceptive use or circulating sex steroids predict complex emotion recognition.

Relatively little is known about the effects of endogenous and exogenous steroid hormones on ecologically relevant behavioral and cognitive phenotypes in women, such as emotion recognition, despite the widespread use of steroid hormone-altering hormonal contraceptives (HCs). Though some previous studies have examined the effect of HC use, estradiol, progesterone, and testosterone on emotion recognition in women, they have been limited by cross-sectional designs, small sample sizes (total n < 100), and compromised statistical power to detect significant effects. Using data from two test sessions in a large sample of naturally cycling women (NC; n = 192) and women on HCs (n = 203), we found no group differences in emotion recognition; further, the lack of group differences in emotion recognition was not modulated by item difficulty or emotional valence. Among NC women who provided saliva samples across two sessions that were assayed for estradiol and progesterone concentrations, we found no compelling evidence across models that between-subject differences and within-subject fluctuations in these ovarian hormones predicted emotion recognition accuracy, with the exception that between-subjects estradiol negatively predicted emotion recognition for emotions of neutral valence (p = .042). Among HC women who provided saliva samples across two sessions that were assayed for testosterone, we found no compelling evidence that between-subjects differences and within-subject fluctuations in testosterone predicted emotion recognition accuracy. Overall, our analyses provide little support for the idea that circulating endogenous or exogenous ovarian hormones influence emotion recognition in women.

Bone health in estrogen-free contraception.

Estrogens and progestogens influence the bone. The major physiological effect of estrogen is the inhibition of bone resorption whereas progestogens exert activity through binding to specific progesterone receptors. New estrogen-free contraceptive and its possible implication on bone turnover are discussed in this review. Insufficient bone acquisition during development and/or accelerated bone loss after attainment of peak bone mass (PBM) are 2 processes that may predispose to fragility fractures in later life. The relative importance of bone acquisition during growth versus bone loss during adulthood for fracture risk has been explored by examining the variability of areal bone mineral density (BMD) (aBMD) values in relation to age. Bone mass acquired at the end of the growth period appears to be more important than bone loss occurring during adult life. The major physiological effect of estrogen is the inhibition of bone resorption. When estrogen transcription possesses binds to the receptors, various genes are activated, and a variety modified. Interleukin 6 (IL-6) stimulates bone resorption, and estrogen blocks osteoblast synthesis of IL-6. Estrogen may also antagonize the IL-6 receptors. Additionally, estrogen inhibits bone resorption by inducing small but cumulative changes in multiple estrogen-dependent regulatory factors including TNF-α and the OPG/RANKL/RANK system. Review on existing data including information about new estrogen-free contraceptives. All progestins exert activity through binding to specific progesterone receptors; hereby, three different groups of progestins exist: pregnanes, gonanes, and estranges. Progestins also comprise specific glucocorticoid, androgen, or mineralocorticoid receptor interactions. Anabolic action of a progestogen may be affected via androgenic, anti-androgenic, or synadrogenic activity. The C 19 nortestosterone class of progestogens is known to bind with more affinity to androgen receptors than the C21 progestins. This article reviews the effect of estrogens and progestogens on bone and presents new data of the currently approved drospirenone-only pill. The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml does not seem to lead to an accelerate bone loss.

CROI 2019: advances in antiretroviral therapy.

The 2019 Conference on Retroviruses and Opportunistic Infections included many exciting advances in antiretroviral therapy (ART). Investigators presented a case report of a second patient possibly cured of HIV through an allogeneic hematopoietic stem cell transplant from a CC chemokine receptor 5-delta 32 donor. Two clinical trials of long-acting injectable cabotegravir and rilpivirine showed promising safety, efficacy, and tolerability as maintenance ART. Test-and-treat and rapid-ART-start strategies show promise in advancing progress toward the HIV care cascade 90-90-90 Joint United Nations Programme on HIV/AIDS/World Health Organization targets. However, late diagnosis and mortality after ART initiation remain high, even in the context of HIV service scale-up, and mortality from unintentional opioid overdose in people living with HIV in the United States is on the rise. In vitro studies were presented that identified and evaluated the effect of resistance-associated mutations on ART susceptibility and elucidated mechanisms of resistance. Epidemiologic data were reported on the prevalence, impact, regional variation, and changes over time of resistance-associated mutations. Decreasing regional and national rates of resistance may be a benefit of increasing use of integrase strand transfer inhibitors (InSTIs). New findings were presented on maternal and fetal health outcomes in women of reproductive potential, drug-drug interactions between hormonal contraception and ART, and further exploration of the association between InSTIs and birth defects.