Hormones and thrombosis: the dark side of the moon.

BACKGROUND: The main drawback of oral contraceptives (OC) and hormone replacement therapy (HRT) is an increased risk of venous and, to a lesser extent, arterial thrombosis. MATERIALS AND METHODS: This narrative, case-based review describes the effect of available estrogens and progestogens on the hemostatic system and their potential impact on the risk of thrombosis. Clinical cases are used to illustrate different options for prescribing OC and HRT in the real-word. The aim is to offer discussion topics that could be helpful to guide the choice of different hormonal treatments over a woman's lifetime and in the presence of risk factors. RESULTS: We describe physio-pathological changes occurring during the administration of hormonal therapies. Furthermore, we analyze the risk of venous and arterial thrombosis associated with different products, routes of administration and additional risk factors. New hormonal preparations, such as estradiol combined with dienogest, as well as non-oral hormonal therapies, are suggested to decrease thrombotic risk significantly. DISCUSSION: The availability of many products and different routes of administration allow most women to safely use contraception, as well as HRT. We encourage careful counselling instead of inflexible or fearful behavior, as expanding options and choices will allow women to make the best decisions for their health.

Lower levels of the neuroprotective tryptophan metabolite, kynurenic acid, in users of estrogen contraceptives.

Changes in kynurenine metabolites are reported in users of estrogen containing contraception. We have assessed kynurenines, vitamin B6, vitamin B2 and the inflammation markers, C-reactive protein (CRP) and neopterin, in healthy, never-pregnant women between 18 and 40 years (n = 123) and related this to their use of hormonal contraception. The population included 58 women, who did not use hormonal contraceptives (non-users), 51 users of estrogen-containing contraceptives (EC-users), and 14 users of progestin only contraceptives (PC-users). EC-users had significantly lower plasma kynurenic acid (KA) and higher xanthurenic acid (XA) levels compared to non-users. Serum CRP was significantly higher and negatively associated with both vitamin B6 and B2 status in EC-user compared to non-users. No significant differences in any parameters were seen between PC-users and non-users (p > 0.1). The low KA and high XA concentration in users of estrogen containing contraception resemble the biochemical profile observed in vitamin B6 deficiency. The hormonal effect may result from interference with the coenzyme function of vitamin B6 and B2 for particular enzymes in the kynurenine metabolism. KA has been suggested to be neuroprotective and the significantly reduced concentration in EC-users may be of importance in the observed increased risk of mood disorders among users of oral contraceptives.

Combined and progestagen-only hormonal contraceptives and breast cancer risk: A UK nested case-control study and meta-analysis.

BACKGROUND: Current or recent use of combined oral contraceptives (containing oestrogen+progestagen) has been associated with a small increase in breast cancer risk. Progestagen-only contraceptive use is increasing, but information on associated risks is limited. We aimed to assess breast cancer risk associated with current or recent use of different types of hormonal contraceptives in premenopausal women, with particular emphasis on progestagen-only preparations. METHODS AND FINDINGS: Hormonal contraceptive prescriptions recorded prospectively in a UK primary care database (Clinical Practice Research Datalink [CPRD]) were compared in a nested case-control study for 9,498 women aged <50 years with incident invasive breast cancer diagnosed in 1996 to 2017, and for 18,171 closely matched controls. On average, 7.3 (standard deviation [SD] 4.6) years of clinical records were available for each case and their matched controls prior to the date of diagnosis. Conditional logistic regression yielded odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by the hormonal contraceptive type last prescribed, controlled for age, GP practice, body mass index, number of recorded births, time since last birth, and alcohol intake. MEDLINE and Embase were searched for observational studies published between 01 January 1995 and 01 November 2022 that reported on the association between current or recent progestagen-only contraceptive use and breast cancer risk in premenopausal women. Fixed effects meta-analyses combined the CPRD results with previously published results from 12 observational studies for progestagen-only preparations. Overall, 44% (4,195/9,498) of women with breast cancer and 39% (7,092/18,171) of matched controls had a hormonal contraceptive prescription an average of 3.1 (SD 3.7) years before breast cancer diagnosis (or equivalent date for controls). About half the prescriptions were for progestagen-only preparations. Breast cancer ORs were similarly and significantly raised if the last hormonal contraceptive prescription was for oral combined, oral progestagen-only, injected progestagen, or progestagen-releasing intrauterine devices (IUDs): ORs = 1.23 (95% CI [1.14 to 1.32]; p < 0.001), 1.26 (95% CI [1.16 to 1.37]; p < 0.001), 1.25 (95% CI [1.07 to 1.45]; p = 0.004), and 1.32 (95% CI [1.17 to 1.49]; p < 0.001), respectively. Our meta-analyses yielded significantly raised relative risks (RRs) for current or recent use of progestagen-only contraceptives: oral = 1.29 (95% CI [1.21 to 1.37]; heterogeneity χ25 = 6.7; p = 0.2), injected = 1.18 (95% CI [1.07 to 1.30]; heterogeneity χ28 = 22.5; p = 0.004), implanted = 1.28 (95% CI [1.08 to 1.51]; heterogeneity χ23 = 7.3; p = 0.06), and IUDs = 1.21 (95% CI [1.14 to 1.28]; heterogeneity χ24 = 7.9; p = 0.1). When the CPRD results were combined with those from previous published findings (which included women from a wider age range), the resulting 15-year absolute excess risk associated with 5 years use of oral combined or progestagen-only contraceptives in high-income countries was estimated at: 8 per 100,000 users from age 16 to 20 years and 265 per 100,000 users from age 35 to 39 years. The main limitation of the study design was that, due to the nature of the CPRD data and most other prescription databases, information on contraceptive use was recorded during a defined period only, with information before entry into the database generally being unavailable. This means that although our findings provide evidence about the short-term associations between hormonal contraceptives and breast cancer risk, they do not provide information regarding longer-term associations, or the impact of total duration of contraceptive use on breast cancer risk. CONCLUSIONS: This study provides important new evidence that current or recent use of progestagen-only contraceptives is associated with a slight increase in breast cancer risk, which does not appear to vary by mode of delivery, and is similar in magnitude to that associated with combined hormonal contraceptives. Given that the underlying risk of breast cancer increases with advancing age, the absolute excess risk associated with use of either type of oral contraceptive is estimated to be smaller in women who use it at younger rather than at older ages. Such risks need be balanced against the benefits of using contraceptives during the childbearing years.

Use of combined hormonal contraception and stroke: A case-control study of the impact of migraine type and estrogen dose on ischemic stroke risk.

OBJECTIVE: To clarify how factors such as estrogen dose and migraine history (including migraine subtype) impact ischemic stroke risks associated with combined hormonal contraceptive (CHC) use. BACKGROUND: CHC use in those with migraine with aura has been restricted due to concerns about stroke risk. METHODS: We conducted a case-control analysis of stroke risk associated with estrogen dose and migraine history among CHC users in a large tertiary care center. All women aged 18-55 who used a CHC between January 1, 2010, and December 31, 2019, were identified. Those with a stroke diagnosis were identified using ICD codes and confirmed via chart and imaging review. Details of personal and family medical history, stroke evaluation, ethinyl estradiol dosing (EE; ≥30 vs. <30 µg), and demographics were collected. From a random sample of 20,000 CHC users without stroke, a control cohort (n = 635) was identified and matched based on patient characteristics, medical and family histories, as well as stroke risk factors, to assess association between migraine diagnosis, migraine subtype, estrogen dose, and stroke. RESULTS: Of the 203,853 CHC users in our cohort, 127 had confirmed stroke (0.06%; CI 0.05%, 0.07%). In unadjusted analyses, a higher number of patients in the case cohort had a diagnosis of migraine (34/127, 26.8%) compared to controls (109/635, 17.2%; p = 0.011). Stroke risk was higher with ≥30-µg EE doses compared to those using a <30-µg dose (OR, 1.52; CI 1.02, 2.26; p = 0.040). Compared to no migraine, personal history of migraine increased the odds of stroke (OR, 2.00; CI 1.27, 3.17; p = 0.003). Compared to no migraine, stroke risk was not significantly increased in those with migraine with aura, but migraine without aura increased the risk (OR, 2.35; CI 1.32, 4.2; p = 0.004). CONCLUSIONS: Overall stroke risk in our cohort of CHC users was low. When CHCs are used in those with migraine, formulations containing ≤30 µg EE are preferred. Shared decision-making should include discussions about ischemic stroke risks in patients with migraine, even those without aura.

Assessment of Hormonal Contraceptive Utilization and Associated Odds of Hypercoagulopathy in Patients with Venous Malformations Using a National Claims Database.

BACKGROUND: Vascular anomalies that exhibit a slow velocity of blood flow, specifically venous malformations (VM), are associated with hypercoagulability. There is limited literature on the utilization of hormonal contraceptives (HCs) and the development of clotting events in female individuals diagnosed with VM. OBJECTIVE: We aimed to characterize HC utilization and associated odds of hypercoagulopathy in patients with VM of child-bearing age. METHODS: Using a national administrative claims database, we identified female patients with VM aged 15-49 years and a control population, matched for age and length of insurance enrollment, from 2016 to 2021. Multivariable logistic regression was used to estimate the odds of hypercoagulation events associated with HC use. RESULTS: Two hundred and sixty-seven (47.2%) patients with VM and 1284 (45.4%) control patients utilized HCs during the study period. Oral contraceptives were the most common HC for patients with and without VM (73.8% and 76.9% of those taking HCs, respectively), and estrogen-containing combination HCs (70.4% in patients with VM and 75.9% in controls) were more prevalent than progestin-only HCs in both populations. Despite a heightened baseline odds of hypercoagulopathy in patients with VM relative to patients without VM (odds ratio = 12.54; 95% confidence interval 7.73-20.3), HC use was not associated with an increased odds of hypercoagulation in the VM subpopulation (odds ratio = 0.82; 95% confidence interval 0.46-1.46). In contrast, tobacco use (odds ratio = 2.12; 95% confidence interval 1.09-4.12) and a history of coagulopathy (odds ratio = 3.92; 95% confidence interval 1.48-10.36) were predictive of thromboembolic events in the VM cohort. CONCLUSIONS: These findings suggest that patients with VM may safely use HCs with careful consideration of other risk factors for thromboses.

Body weight changes and duration of estrogen exposure modulate the evolution of hepatocellular adenomas after contraception discontinuation.

BACKGROUND AND AIMS: The natural history of hepatocellular adenomas (HCAs) remains to be better described, especially in nonresected patients. We aim to identify the predictive factors of HCA evolution after estrogen-based contraception discontinuation. APPROACH AND RESULTS: We retrospectively included patients with a histological diagnosis of HCA from three centers. Clinical, radiological, and pathological data were collected to identify predictive factors of radiological evolution per Response Evaluation Criteria in Solid Tumors, version 1.1, and occurrence of complications (bleeding, malignant transformation). We built a score using variables that modulate estrogen levels: body mass index and duration of estrogen-based contraception. An external cohort was used to validate this score. 183 patients were included in the cohort, including 161 women (89%) using estrogen-based contraception for a median of 12 years. Thirty percent of patients had at least one HNF1A -inactivated HCA, 45.5% at least one inflammatory HCA, and 11% at least one HCA with activation of ß-catenin (bHCA). Twenty-one symptomatic bleedings (11%) and eleven malignant transformations (6%) occurred. Ages < 37 years old ( p = 0.004) and HCA > 5 cm at imaging were independently associated with symptomatic bleeding ( p = 0.003), whereas a bHCA was associated with malignant transformation ( p < 0.001). After a median follow-up of 5 years, radiological regression was observed in 31%, stabilization in 47%, and progression in 22% of patients. Weight loss was associated with regression ( p < 0.0001) and weight gain with progression ( p = 0.02). The estrogen exposure score predicted radiological regression (odds ratio, 2.33; confidence interval 95%, 1.29-4.19; p = 0.005) with a linear relationship between the rate of estrogen exposure and the probability of regression. This result was confirmed in an external cohort of 72 female patients ( p = 0.003). CONCLUSION: Weight variation is strongly associated with radiological evolution after oral contraception discontinuation. A score of estrogen exposure, easily assessable in clinical practice at diagnosis, predicts regression of HCA.

Influence of progestin-only hormonal use on hepatocellular adenomas: A retrospective cohort study.

OBJECTIVES: Exogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients. STUDY DESIGN: In this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures. RESULTS: A total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only). CONCLUSIONS: During discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception. IMPLICATIONS: In this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.

[Neuropsychological side effects of combined hormonal contraceptives for the treatment of mild symptoms. Bioethical assessment of its adequacy]. / Efectos secundarios neuropsicológicos de los anticonceptivos hormonales combinados para el tratamiento de síntomas leves. Valoración bioética de su adecuación.

Since the beginning of the commercialization, in 1960, of combined estrogen-progestin hormonal contraceptives (CHCs), their use has become widespread for other non-contraceptive indications: dysmenorrhea, irregular cycle length, hypermenorrhea and acne, among others (Lete, 2009; Barranco, 2016). In all cases, these are mild pathologies or minor symptoms for which there are effective therapeutic alternatives. Millions of women in the world receive this treatment, which acts by inhibiting the hypothalamic-pituitary-ovarian hormonal axis (HHO Axis), the central axis and regulator of the entire sexual and reproductive physiology of women. Despite the existence of an enormous number of women subjected to this inhibition (ACHs are currently used by some 214 million women around the world, with an annual market of close to 18 billion dollars), very little research has been done on the consequences of suppressing the HHO axis. Only in recent years, and in parallel to the demonstration of the existence of functional receptors for gonadotropins at different levels in the central and peripheral nervous systems, have publications on the neuropsychological effects of HCAs begun to appear. It is also striking that, despite being the most widely used drugs and for the longest time for the treatment of functional gynecological disorders, their use is outside the technical data sheet (i.e., they are used for purposes other than those listed in the official indication approved in their technical data sheet and which appear in the package insert). Although the use of these hormonal products causes a wide variety of side effects, which have been widely studied in the medical literature, the present study proposes, after an exposition of the different aspects of the use of HCAs, a detailed review of the available literature on the neuropsychological effects due to the annulment of the HHO axis. This in order to, after a biological analysis, subsequently establish whether there is an ethical appropriateness in the use that concerns us.

[Contraception and Sexual Health]. / Kontrazeption und Sexualität.

Contraception and Sexual Health Abstract. Reliable contraceptive methods allow a free development of sexuality without fear of unwanted pregnancies. They have contributed significantly to a more self-determined sexuality of both women and men at reproductive age. Hormonal contraceptives, which are available in different compositions and application forms, are highly effective, but are nevertheless used less and less for fear of physical and psychological side effects. Current study data regarding sexual health is heterogenous but reflects the clinical experience that hormonal contraceptives usually have no significant effect. However, some women report improved sexual experience, while others suffer from sexual dysfunction. Hormonal contraceptives act primarily on the hypothalamic-pituitary-ovarian axis to prevent folliculogenesis and ovulation. However, they have an effect on all tissues with sex steroid receptors, including peripheral tissues such as genitals, skin. But they also have an effect on neurobiological mechanisms (mainly in the hypothalamic region) essential for human sexual response. They can impact self and partnership perception, libido, and arousal. The observed influences can be explained via various mechanisms such as: lack of fear of unwanted pregnancies and accordingly more liberated sexuality, decrease in gynecological complaints, such as endometriosis-associated dyspareunia or dysmenorrhea, possible improvement of the individual body image (subjective perception of the physical self) and correspondingly improved self-confidence (e.g., by decreasing acne and hirsutism). Individualized contraceptive counselling, taking into account somatic and emotional aspects, is essential and can contribute to the promotion of sexual health and well-being. This review article summarizes the influence of hormonal contraceptive methods on sexual health and well-being and gives recommendations how to deal with contraception-induced sexual dysfunction.

[Mifepristone: from pre- to post-protection]. / Mifepriston: van voor- tot nabehoeden.

All current hormonal contraceptives have side effects and contraindications related to estrogens and progestins. Users are often dissatisfied with this. There is a great need for a new contraceptive drug without these hormones with the associated side effects and contraindications; with also a favorable bleeding profile; that can be used orally and not daily; that can serve as a contraceptive and after-care and can also be used on demand. Mifepristone 50 mg seems to provide the answer to all these wishes but is not (yet) registered in the Netherlands.

Hormonal contraceptives, stress, and the brain: The critical need for animal models.

Hormonal contraceptives are among the most important health and economic developments in the 20thCentury, providing unprecedented reproductive control and a range of health benefits including decreased premenstrual symptoms and protections against various cancers. Hormonal contraceptives modulate neural function and stress responsivity. These changes are usually innocuous or even beneficial, including their effects onmood. However, in approximately 4-10% of users, or up to 30 million people at any given time, hormonal contraceptives trigger depression or anxiety symptoms. How hormonal contraceptives contribute to these responses and who is at risk for adverse outcomes remain unknown. In this paper, we discussstudies of hormonal contraceptive use in humans and describe the ways in which laboratory animal models of contraceptive hormone exposure will be an essential tool for expanding findings to understand the precise mechanisms by which hormonal contraceptives influence the brain, stress responses, and depression risk.

Progestins of today and tomorrow.

PURPOSE OF REVIEW: To review the current literature on the multiple types and uses of progestins in reproductive healthcare. RECENT FINDINGS: Progestins for contraceptive use are available in multiple forms, with the ongoing development of transdermal, intravaginal, and male contraception formulations. Noncontraceptive use of progestins often overlaps with contraceptive indications, which allows for simultaneous multipurpose progestin use, especially in reproductive-aged patients. More studies are needed to determine contraceptive doses of progestins used for noncontraceptive purposes. Side effect profiles of progestins are dependent on their formulation and cross-reactivity with other steroid receptors. Development of newer progestins includes manipulating pharmacologic properties to avoid undesired side effects. SUMMARY: Progestins have multiple uses in reproductive healthcare, including contraception, menstrual suppression, endometrial protection, and hormonal replacement therapy. The development of progestins for these indications can expand therapy for people with contraindications to estrogen-based hormonal therapy.

Systemic hormonal contraception and risk of venous thromboembolism.

INTRODUCTION: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. MATERIAL AND METHODS: All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. RESULTS: Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). CONCLUSIONS: An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.

Hormonal contraception use before and after breast cancer diagnosis: A nationwide drug utilization study.

PURPOSE: To describe the use of hormonal contraceptives in Danish breast cancer patients. METHODS: Nationwide drug utilization study in Danish women diagnosed with breast cancer at ages 13-50 years during 2000-2015. User proportions were estimated in 6-months intervals from 2 years before to 2 years after diagnosis. RESULTS: Use of hormonal contraceptives declined sharply after breast cancer diagnosis. Still, 7% of patients aged 13-39 years filled hormonal contraceptive prescriptions within 6 months after the diagnosis. CONCLUSIONS: The majority of premenopausal breast cancer patients discontinues hormonal contraception at diagnosis. All prescribers of hormonal contraceptives should acknowledge that hormonal contraception is contraindicated for breast cancer patients. PLAIN LANGUAGE SUMMARY: Use of hormonal contraception is contraindicated among women with breast cancer. In this nationwide study, we assessed the use of hormonal contraceptives among all Danish premenopausal women diagnosed with breast cancer during 2000-2015. Hormonal contraceptive use was assessed within 2 years before and 2 years after breast cancer diagnosis. The majority of patients discontinued hormonal contraception at breast cancer diagnosis. However, 7% of patients aged 13-39 years filled hormonal contraceptive prescriptions within 6 months after the diagnosis.

Risk of recurrence in women with venous thromboembolism related to estrogen-containing contraceptives: Systematic review and meta-analysis.

BACKGROUND: The risk of recurrence after a venous thromboembolism (VTE) related to estrogen-containing contraceptives is a key driver to guide anticoagulant treatment decisions. OBJECTIVE: To estimate the incidence rate of recurrent VTE after discontinuation of anticoagulant treatment in women with a first episode of VTE related to estrogen-containing contraceptives. METHODS: Embase, MEDLINE, and the CENTRAL were searched from 1 January 2008 to 27 May 2021 for prospective and retrospective studies reporting on recurrence after a first VTE related to estrogen-containing contraceptives. Risk of bias was assessed using QUIPS tool. Recurrence rates per 100 patient-years were pooled using Knapp-Hartung random-effects meta-analysis. Incidence rates were reported separately based on study follow-up duration (≤1 year, 1-5 years, and >5 years) and for several subgroups. RESULTS: A total of 4,120 studies were identified, of which 14 were included. The pooled recurrence rate was 1.57 (95%-CI: 1.10-2.23; I2  = 82%) per 100 patient-years. Recurrence rates per 100 patient-years were 2.73 (95%-CI: 0.00-3643; I2  = 80%) for studies with ≤1 year follow-up, 1.35 (95%-CI: 0.68-2.68; I2  = 44%) for studies with 1-5 years follow-up, and 1.42 (95%-CI: 0.84-2.42; I2  = 78%) for studies with >5 years follow-up. CONCLUSION: Among women with VTE associated with estrogen-containing contraceptives, the risk of recurrence after stopping anticoagulation is low, which favors short-term anticoagulation. Large prospective studies on VTE recurrence rates and risk factors after stopping short-term anticoagulants are needed.

[The risk-benefit balance of estrogen-progestogen hormonal contraception]. / La balance bénéfices-risques des contraceptions hormonales estroprogestatives.

Combined hormonal contraception (CHC) remains the most widely used contraceptive strategy, particularly in France. While the benefit-risk balance is very beneficial for the majority of women, its use must be cautious in some clinical situations and in particular in women at vascular risk. It is therefore essential to provide information on all the vascular risk factors before prescribing any CHC, regardless of their route of administration. From an oncological point of view, if the use of CHCs is associated with a slight increase in the risk of breast cancer, their potential benefits persist for many years after their discontinuation for the risk of ovarian and endometrial cancer. These benefits counteract largely the risk of breast cancer. Finally, CHCs provide non-contraceptive benefits, especially in clinical situations such as dysmenorrhea or severe endometriosis. Therefore, it is necessary to precisely assess the clinical context of each woman in order to adapt the best contraceptive strategy.

TITLE: La balance bénéfices-risques des contraceptions hormonales estroprogestatives. ABSTRACT: La contraception hormonale estroprogestative (COP) reste la stratégie contraceptive la plus utilisée, notamment en France. Si la balance bénéfices-risques est, pour la très grande majorité des femmes, très favorable, son utilisation doit être extrêmement prudente dans certaines situations cliniques et, en particulier, chez les femmes à risque vasculaire. Il est donc indispensable de renseigner l'ensemble des facteurs de risque vasculaire avant toute prescription de COP, quelle que soit sa voie d'administration. D'un point de vue carcinologique, si l'utilisation de la COP est associée à une discrète augmentation du risque de cancer du sein, les bénéfices méconnus, persistant de nombreuses années après son arrêt, vis-à-vis du risque de cancer de l'ovaire et de l'endomètre, contrebalancent largement ce risque mammaire. Enfin, la COP apporte des avantages non contraceptifs, notamment dans les situations cliniques telles que les dysménorrhées ou l'endométriose invalidante, améliorant profondément la qualité de vie des femmes. Il est donc nécessaire d'évaluer très précisément le contexte clinique de chaque femme afin d'adapter la meilleure stratégie contraceptive en minimisant les risques et pour bénéficier des avantages potentiels.

Estrogen and Progesterone Therapy and Meningiomas.

Meningiomas are common intracranial tumors with a female predominance. Their etiology is still poorly documented. The role of sexual hormones has long been evoked, and data have been conflicting across studies. However, a dose-dependent relationship between the incidence and growth of meningiomas and hormonal treatment with the progestin cyproterone acetate (CPA) has recently been established. CPA-associated meningiomas seem to be mainly located in the anterior and middle skull base, are more likely to be multiple, may harbor P1K3CA mutations in up to one-third of cases, and are more common with a longer duration of treatment. A similar but lower risk of meningiomas has been recently reported with the use of chlormadinone acetate and nomegestrol acetate as progestin treatments. Concerning hormonal replacement therapy (HRT) in menopausal patients, evidence from epidemiological studies seem to favor an increased risk of meningiomas in treated patients although a recent study failed to show an increased growth of meningiomas in HRT treated vs nontreated patients. Until larger studies are available, it seems wise to recommend avoiding HRT in patients with meningiomas. Evidence from published data does not seem to support an increased risk of meningiomas with oral contraceptive oral contraceptive (OR) use. Data are too scarce to conclude on fertility treatments. Based on studies demonstrating the expression of hormonal receptors in meningiomas, therapies targeting these receptors have been tried but have failed to show an overall favorable clinical outcome in meningioma treatment.

The relationship between hormonal contraception and cervical dysplasia/cancer controlling for human papillomavirus infection: A systematic review.

OBJECTIVE: Studies on the effect of long-term use of combined oral contraceptives (COCs) on cervical dysplasia and/or cancer risk have been inconsistent. Less is known about the effects of other forms of hormonal contraception (HC). We examine whether HC use increases the risk of incident cervical intraepithelial neoplasia (CIN) 2, 3 and/or cancer after accounting for preexisting human papillomavirus (HPV) infection. STUDY DESIGN: Systematic review of prospective studies on HC use as risk factor for cervical dysplasia with HPV infection documented prior to outcome assessment including PubMed and EMBASE records between January 2000 and February 2020 (Prospero #CRD42019130725). RESULTS: Among nine eligible studies, seven described recency and type of HC use and therefore comprise the primary analysis; two studies limit comparisons to ever versus never use and are summarized separately. All seven studies explored the relationship between oral contraceptive (OC) use and cervical dysplasia/cancer incidence: two found increased risk (adjusted odds ratio, aOR = 1.5-2.7), one found no association but decreased risk when restricted to women with persistent HPV (adjusted hazard ratio = 0.5), and four found no association. None of the seven studies differentiated between COC and progestin-only pills (POPs) by use recency or duration. The only study that included injectable progestin-only contraception (DMPA) found increased CIN3 incidence among current versus never users (aOR = 1.6). The one study that included Norplant found no association. Two studies included intrauterine device (IUD) use, but did not differentiate between hormonal and copper IUDs, and found no association. CONCLUSION: We found no consistent evidence that OC use is associated with increased risk for cervical dysplasia/cancer after controlling for HPV infection. There were too few studies of progestin-only injectables, implants or IUDs to assess their effect on cervical dysplasia/cancer risk. IMPLICATIONS: Use of single self-reported HC measures and insufficient distinction by hormonal constituent cloud our understanding of whether some HCs increase risk for cervical cancer. Methodologically rigorous studies with distinct HCs measured as time-varying exposures are needed to inform cervical cancer prevention efforts and improve our understanding of cervical cancer etiology.

[Contraception in women with obesity]. / Contraception dans le contexte de l'obésité.

Obese women are at high risk of unintended pregnancy. In addition, obesity is an important risk factor for venous thromboembolism events and arterial thrombosis. All of these data are to be considered in choosing a contraceptive method for obese women. The metabolic changes and the increased body mass of these women may be the cause of a reduction in the effectiveness of hormonal contraception. The progestin-only contraceptives (progestin only pills and etonogestrel subdermal implant) and the intra-uterine devices are the preferred contraceptive methods in women with obesity. The combined estrogen-progestin contraceptives may be proposed in young obese women without other cardiovascular risk factor. Obesity per se does not seem to increase the risk of failure of most contraceptive methods. Bariatric surgery is a complex situation. Contraception is needed for at least 12 months after surgery. Some bariatric surgery such as bypass can induce gastrointestinal malabsorption. In this situation, all oral contraceptives are not recommended because of a higher risk of failure.

TITLE: Contraception dans le contexte de l'obésité. ABSTRACT: La question de l'influence de l'obésité sur la contraception peut être envisagée sous plusieurs angles : comme facteur de risque d'échec d'une contraception hormonale ; comme facteur de risque cardio-vasculaire, pouvant majorer ce risque lors de l'association à une contraception hormonale. Les modifications métaboliques observées au cours de l'obésité et la masse corporelle plus importante des femmes présentant une obésité peuvent en effet être à l'origine d'une réduction de l'efficacité de la contraception hormonale. Néanmoins, les données, mêmes peu nombreuses, laissent penser que l'efficacité de la plupart des méthodes de contraception n'est a priori pas diminuée chez ces femmes. La chirurgie bariatrique, utilisée pour remédier à l'obésité, constitue une situation complexe, qui impose une contraception dans la première année post-opératoire afin d'éviter toute grossesse. Si la technique chirurgicale induit une malabsorption (comme le bypass), toute contraception administrée par voie orale verra son efficacité fortement diminuée et sera donc déconseillée en raison d'un haut risque d'échec.