Progestogen-only Research Articles

Thrombotic risks of oral contraceptives

To inform about the risk of venous thromboembolism (VTE) of different hormonal contraceptives in different patient groups. Combined oral contraceptives (COCs) differ significantly regarding VTE risk depending on amount of estrogen and type of progestogen: COCs containing desogestrol, gestoden or drospirenone in combination with ethinylestradiol (so called third-generation or fourth-generation COCs) are associated with a higher VTE risk than COCs with ethinylestradiol and levonorgestrel or norethisterone (so called second-generation COCs). The VTE risk for transdermal COCs like vaginal ring (NuvaRing) or patch (Evra) is as high as for COCs of third or fourth generation. Progestogen-only contraceptive methods do not increase VTE risk significantly. New kinds of COC without ethinylestradiol but with estradiol valerat or estradiol showed a much lower degree of coagulation activation than 'classical' COC containing ethinylestradiol. Second-generation COCs should be the first choice when prescribing hormonal contraception.In patients with a history of VTE and/or a known thrombophilic defect, COCs are contraindicated, but progestogen-only contraceptives can be safely used in this patient group. Whether newer COCs with estradiol valerate or estradiol have a lower VTE risk remains to be elucidated.

User characteristics and out-of-pocket expenditures for progestin-only versus combined oral contraceptives

BackgroundLittle is known about the proportion of oral contraceptive pill (OCP) users that use progestin-only pills (POPs), factors associated with POP use, and whether out-of-pocket expenditures and dispensing patterns are similar to combined oral contraceptives (COCs). Study DesignObservational cohort using 1996–2008 Medical Expenditure Panel Surveys. ResultsAmong all OCP users, 4% used POPs and changed little between 1996 and 2008. Women were more likely to use POPs if they received postpartum care (p<.001), had a diagnosis of hypertension (p<.001) or resided in the West (p<.01). POP users, compared to COC users, were more likely to pay $15 and more (p<.01) and less likely to obtain more than one pack per purchase (p<.001), controlling for age, race/ethnicity and insurance coverage. ConclusionPOP use is very low in the United States. POP users obtained fewer packs per purchase compared with COC users, suggesting that POP may be used as transitional OCPs, particularly during the postpartum period.

Hormonal contraception and venous thromboembolism

New studies about the influence of hormonal contraception on the risk of venous thromboembolism (VTE) have been published. To evaluate new epidemiological data and to propose clinical consequences. A literature survey. Studies assessing the risk of specific types of hormonal contraception were evaluated, compared and set into a clinical perspective. The majority of newer studies have demonstrated a threefold increased risk of VTE in current users of medium- and low-dose combined oral contraceptives (COCs) with norethisterone, levonorgestrel (LNG) or norgestimate compared with non-users. The same studies have demonstrated a sixfold increased risk of VTE in users of combined pills with desogestrel, gestodene, drospirenone or cyproteroneacetate, and in users of the contraceptive vaginal ring, compared with non-users. The rate ratio of VTE between users of COCs with newer progestogens compared with users of COCs with LNG was 1.5-2.8 in seven studies and 1.0 in two studies. Progestogen-only contraception did not confer an increased risk of VTE in any study. The incidence rate of VTE in non-pregnant women aged 15-49 years using non-hormonal contraception is three per 10 000 years. For women starting on hormonal contraception, we recommend medium- or low-dose combined pills with norethisterone, LNG or norgestimate as first-choice preparations. For the many women who are users of COCs with newer progestogens, although the absolute risk of VTE is low, a change to combined pills with norethisterone, LNG or norgestimate may halve their risk of VTE. Finally, we recommend COCs with 20 μg estrogen combined with the older progestogens to be launched in the Scandinavian countries. Women at an increased risk of VTE should consider progestogen-only contraception or non-hormonal contraception.

Cancer and contraception: Release date May 2012 SFP Guideline #20121

As a result of advances in cancer diagnosis and treatment, young women within the reproductive-aged group are now more likely to survive cancer. Reproductive-aged women with cancer may be interested in deferring pregnancy either temporarily or permanently at cancer diagnosis, during therapy or after treatment. Currently, there are limited guidelines to aide clinicians in managing the contraceptive needs in this special population. After reviewing the evidence regarding the safety and efficacy of available methods of contraception for women who have been diagnosed with cancer, the Society of Family Planning recommends that women of childbearing age who are being treated for cancer avoid combined hormonal contraceptive methods (containing estrogen and progestin) when possible because they may further increase the risk of venous thromboembolism (VTE) (Level A). The copper T380A intrauterine device, a highly effective, reversible, long-acting, hormone-free method, should be considered the first-line contraceptive option for women with a history of breast cancer (Level A), although for women being treated with tamoxifen, the levonorgestrel-containing intrauterine system (IUS) which decreases endometrial proliferation may be preferable (Level B). Women who develop anemia may benefit from use of a progestin-containing contraceptive (Level A). Women who develop osteopenia or osteoporosis following chemotherapy should avoid the progestin-only contraceptive injection (Level B).More information is needed in many areas. There are insufficient data to evaluate the risk of VTE when progestin-only contraceptives are used by women at high risk of VTE. Information is also needed on whether the levonorgestrel-containing IUS affects the risk of breast cancer recurrence and whether hormonal contraceptives affect the risk of breast cancer among women who have received chest wall, or “mantle field,” radiation. Finally, studies of the safety and effectiveness of IUS use by women who are immunosuppressed and studies of whether progestin-only contraceptives affect the risk of fracture among cancer survivors or, more generally, women with osteopenia would be useful.

Slovenian guidelines for progestogen-only oral contraceptive use

In the manuscript the Slovenian guidelines for progestogen-only oral contraceptive use are presented. They are based on WHO, FSRH and CDC guidelines, and were approved in January 2012.

Effects of Etonogestrel Treatment in the Reproductive Organs and Uterine Arteries of Nonoophorectomized Guinea Pigs

The endometria of women treated with long-term progestin-only contraceptives (LTPOCs) display abnormally enlarged, fragile blood vessels, decreased endometrial blood flow, oxidative stress, and unpredictable focal abnormal endometrial bleeding. Because human studies on the effects of LTPOC treatment are constrained for ethical and practical reasons, we assessed the suitability of nonoophorectomized guinea pigs (GPs) to best mimic the hormonal milieu of women. The present study demonstrates that treatment of GPs parallels the morphological changes following LTPOC treatment of the human endometrium and ovaries. Specifically, treatment resulted in larger hyperemic, uteri compared with controls. Histopathologic and immunohistochemical analysis demonstrated fewer endometrial glands, decreased luminal mucus, increased numbers of blood vessels, and focal hemorrhage. While increased staining for the cell mitosis marker, Ki67, was present in the zona functionalis, no such increase occurred in the basalis. Lastly, effects on vasomotor features of uterine arteries suggest changes that favor increased resistance and reduced blood flow promoting decreased ability to withstand elevations in transmural pressure.

Progestin-only contraception and venous thromboembolism

Combined oral contraceptives (COC) are the most popular contraceptive method in developed countries. Since their introduction there have been numerous changes and modifications in its composition with the aim to improve safety and tolerability while maintaining contraceptive efficacy. Most of the changes have been conducted on the progestin component, since most of the combinations include ethinyl estradiol as oestrogen. One of the adverse effects of COC is the increased risk of venous thromboembolism (VTE) in two clinical forms of presentation: deep vein thrombosis or pulmonary embolism. This review details the changes in haemostasis induced by progestin-only contraceptives and the risk of VTE in women who utilize this type of contraception; the relationship with other risk factors such as thrombophilia; the interactions of these contraceptives with anticoagulant treatment and finally the eligibility criteria for the use of hormonal contraception in women with previous VTE or thrombophilia carriers.

Differences in prescription rates and odds ratios of antidepressant drugs in relation to individual hormonal contraceptives: A nationwide population-based study with age-specific analyses

ABSTRACTObjectives To examine, among young women, the association of individual hormonal contraceptives, within two broad groupings, with antidepressant therapy.Methods In a nationwide register-based study, we examined the prescription rates of antidepressant drugs in relation to individual combined hormonal and progestin-only contraceptives among Swedish women aged 16–31 years (N = 917,993). Drug data were obtained from the Swedish Prescribed Drug Register for the period 1 July 2005–30 June 2008. Data on the total population of women aged 16–31 in 2008 were obtained from the Total Population Register of Statistics Sweden. The proportion of women using both hormonal contraception and antidepressants, and odds ratios (ORs) for antidepressant use for hormonal contraceptive users versus non-users, were calculated, the latter by logistic regression, for each formulation.Results The highest antidepressant OR in all age groups, particularly in the 16–19 years age group, related to medroxyprogesterone-only, followed by etonogestrel-only, levonorgestrel-only and ethinylestradiol/norelgestromin formulations. Oral contraceptives containing ethinylestradiol combined with lynestrenol or drospirenone had considerably higher ORs than other pills. ORs significantly lower than 1 were observed when ethinylestradiol was combined with norethisterone, levonorgestrel or desogestrel.Conclusion The association between use of hormonal contraceptives and antidepressant drugs varies considerably within both the combined hormonal contraceptive and the progestin-only groups.

Hormonal contraception in thrombophilic adolescents

SummaryAbout 3.2 million women in Germany are between 14 and 19 years old representing about 19% of women. 55% of them use combined oral contraception (COC). The risk of venous thromboembolism (VTE) during the use of COC is increased 2–6 times. For thrombophilic patients depending on the kind of thrombophilic defect it is much higher. Pregnancy and postpartum period lead to a much higher increase of VTE than any COC use at all, both in women with and without thrombophilic defect. VTE risk in COC is highly dependent on the content of ethinylestradiol (EE) and the kind of progestagen used in COC. Progestagen-only contraceptives (POC) do not increase the VTE risk, since they do not activate the coagulation system. Conclusion: It is not justified to withhold any hormonal contraception to thrombophilic women, especially considering the much higher VTE risk in (maybe unintended) pregnancy. Adolescents thrombophilic women should rather be informed about the opportunity to use POC.

Exploring Contraceptive Options for Breastfeeding Mothers

This editorial discusses the current evidence of which contraceptive options are compatible for successful breastfeeding. It highlights progestin-only contraceptives combined oral contraceptives and combined hormonal contraceptives and provides recommendations for breastfeeding women.

Progestin-Only Contraceptives and the Risk of Venous Thromboembolism: Systematic Review and Meta-Analysis,

Abstract 3344 Background:Combined oral contraceptives (COC) containing estrogens and progestins are associated with a 2 to 4-fold increased risk of venous thromboembolic events. Progestin-only contraceptives are commonly prescribed to women with a higher risk for thrombosis, although a lower thrombotic risk than COC has not been clearly established. We performed a systematic review and meta-analysis of published studies to estimate the risk ratio of venous thromboembolism (VTE) in women taking progesterone for the purpose of contraception. Materials and methods:We performed a literature search of cohort, case-control and randomized studies including women treated with progestin-only contraception compared with a no-hormone control group. All administration routes (oral, injectable and intra-uterine) were considered. The primary endpoint was the corrected risk ratio of VTE analyzed using a random effects model. Results:1150 references were retrieved; 7 studies were retained for analysis. The summary estimate of the adjusted risk ratio of VTE for women taking a progestin for contraception versus no hormone was 1.02 (95% CI=0.76–1.37, p=0.89). Heterogeneity between studies was minimal (Q-value=7.1, I2=15.49 and p=0.31). An analysis combining the unadjusted odds ratios of VTE gave a similar result (OR=1.24, 95% CI=0.93–1.66, p=0.14). Analysis by subgroup suggests a higher risk of thrombotic events for individuals using an injectable progestin, with an estimated risk ratio of VTE equal to 2.67 (95% CI=1.29–5.53, p=0.008), compared to 0.87 (95% CI=0.53–1.42, p=0.58) for oral administration. Conclusions:Progestin-only oral formulations used for contraception do not appear to increase the risk of venous thromboembolic disease, although injectable administration was associated with an increased incidence of VTE relative to women not taking hormones that is comparable to the risk associated with COC.StudyFormatDrug Formulation(s)Number of PatientsAdjusted Risk Ratio of VTE (95% CI)‡ProgestinNo HormoneVTENo VTEVTENo VTE1. Barsoum et al, Thromb Res 2010case-controlO, I32981331.20 (0.40–3.62)2. Conard et al, Contraception 2004retrospective cohortO3996960.80 (0.18–3.53)3. Heinemann et al, Eur J Contracept Reprod Health Care 1999case controlO75417413460.68 (0.28–1.66)4. Lidegaard et al, BMJ 2009retrospective cohortO,U49N/A*2168N/A†0.82 (0.62–1.08)5. Vasilakis et al, Lancet 1999case-controlO, I226131611.30 (0.27–6.19)6. Vlieg et al, Arterioscler Thromb Vasc Bio 2010case-controlI, U234142111021.38 (0.65–2.90)7. WHO, Contraception 1998case-controlO, I329863522881.93 (0.97–3.84)Table Legend: O=oral, I=injectable, U=intra-uterine.*VTE incidence rate/10000 woman years =1.82 to 3.35, depending on the type of progestin.†VTE incidence rate/10000 woman years =3.01 for non-users.‡Odds ratios and rate ratios were treated as risk ratios because of the low prevalence of disease. [Display omitted] Estimated risk ratio of VTE for progestin versus no hormone, using adjusted values; A, all routes of administration for all studies; B, injectable progestins only, for studies where those results were reported.This publication was supported by Grant Number UL1 RR025752 from the National Center for Research Resources. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR. Disclosures:No relevant conflicts of interest to declare.

Progestin-only contraception prevents bone loss in postpartum breastfeeding women

BackgroundThere are an increase in bone loss during the first 6 months postpartum and a complete recovery postweaning. A few studies of steroid contraceptive use during this period provide some evidence towards protection of bone loss with progestin-only contraceptive methods. ObjectiveThe study was conducted to evaluate forearm bone mineral density (BMD) of breastfeeding postpartum women using nonhormonal and progestin-only contraceptive methods. Study DesignA prospective cohort study of postpartum women had an analysis performed at 6 months postpartum correlating BMD with contraceptive use. Forearm BMD was measured 7–10 days, 3 months and 6 months postpartum. Eighty-two women were analyzed, comparing nonhormonal (54) and progestin-only (28) contraceptive methods. Information about breastfeeding duration, amenorrhea and body mass index was collected. ResultsBaseline characteristics of the study population showed no statistical differences between the groups. The median duration of breastfeeding for both groups was 183 days. A significant BMD decrease was observed for the nonhormonal group (p<.001); however, no statistical difference was detected for the progestin-only group. Body mass index, BMD at 7–10 days postpartum and total duration of breastfeeding were positively correlated with BMD at 6 months. ConclusionsOur findings suggest a preventive effect towards postpartum bone loss with progestin-only contraception in breastfeeding women.

Oral contraceptive and progestin-only use correlates to tissue tumor marker expression in women with cervical intraepithelial neoplasia

BackgroundThe study was conducted to investigate correlations between combined oral contraceptive (COC), any progestin-only contraceptive, medicated intrauterine device (MID) or systemic progestin-only (Syst-P) use and tumor marker expression in cervical intraepithelial neoplasia compared to nonusers. Study DesignOne-hundred ninety-five women of fertile age with cervical biopsies ranging histologically from normal epithelium to carcinoma in situ were recruited consecutively. Combined oral contraceptive, Syst-P and MID users were investigated according to the expression of 11 tumor markers. ResultsOverexpression of cyclooxygenase-2 (Cox-2) was observed in COC users, while interleukin 10 was underexpressed. When users of progestogen-only contraceptives were analyzed, there was a lower expression of cytokeratin 10 and interleukin 10. When only MID users were analyzed, a high expression of p53 was found. Expression of Cox-2, p53 and retinoblastoma protein differed between COC and MID users. ConclusionThe study showed molecular alterations, which, in general, have not been studied previously in COC users and have never been studied in progestogen-only users. These biological events might be involved in epidemiological correlations found between hormonal contraceptive use and cervical neoplasms.

Weight change in users of three progestin-only contraception methods

The aim of this study was to compare the change in weight over the first 12 months of use between users of etonogestrel subdermal implant (ENG implant), depot medroxyprogesterone acetate (DMPA) or levonorgestrel intrauterine contraception (LNG-IUC), and the copper intrauterine device (copper-IUC). Our hypothesis was that weight gain will be greater in DMPA, LNG-IUC and ENG implant users compared to copper-IUC users after the first 12 months of use.

Update on hormonal contraception and bone density

Combination hormonal contraception and progestin-only contraception (including depot medroxyprogesterone acetate [DMPA]) are effective and convenient forms of reversible contraception that millions of women use worldwide. In recent years, observations of reduced bone mineral density in current users of these methods have led to concerns that this hormone-induced bone loss might translate into long-term increased fracture risk. Special focus has been placed on adolescent users who have not yet attained their peak bone mass as well as perimenopausal users. In 2004, the FDA added a black box warning to DMPA package labeling warning of the risk of significant bone loss and cautioning against long-term use (> 2 years). This article reviews evidence on the use of hormonal contraception and its effect on bone density in adolescent, premenopausal, and perimenopausal populations. Recommendations from reproductive healthcare organizations are reviewed and clinical recommendations are provided.

Progestin-only contraceptives: effects on weight.

Progestin-only contraceptives (POCs) are appropriate for many women who cannot or should not take estrogen. Many POCs are long-acting, cost-effective methods of preventing pregnancy. However, concern about weight gain can deter the initiation of contraceptives and cause early discontinuation among users. The primary objective was to evaluate the association between progestin-only contraceptive use and changes in body weight. We searched MEDLINE, CENTRAL, POPLINE, EMBASE, LILACS, ClinicalTrials.gov, and ICTRP, and contacted investigators to identify other trials. All comparative studies were eligible that examined a POC versus another method or no contraceptive. The primary outcome was mean change in body weight or body composition. Two authors extracted the data. We computed the mean difference with 95% confidence interval (CI) for continuous variables and odds ratio with 95% CI for dichotomous variables. We did not conduct meta-analysis due to the various contraceptive methods and weight change measures. Fifteen studies examined progestin-only pills (N=1), Norplant (N=4), and depot medroxyprogesterone acetate (DMPA) (N=10). Comparison groups were similar for weight change in 11 studies. Four studies showed differences in weight or body composition change for POCs compared to no hormonal method. Adolescents using DMPA had a greater increase in body fat (%) versus a group using no hormonal method (mean difference 11.00; 95% CI 2.64 to 19.36). The DMPA group also had a greater decrease in lean body mass (%) (mean difference -4.00; 95% CI -6.93 to -1.07). In another study, weight gain (kg) was greater for the DMPA group than an IUD group (mean difference 2.28, 2.71, 3.17, respectively). The differences were notable within the normal weight and overweight subgroups. One study showed the Norplant (six-capsule) group had greater weight gain (kg) than a non-hormonal IUD group (mean difference 0.47 (95% CI 0.29 to 0.65) and a group using non-hormonal or no method (mean difference 0.74; 95% CI 0.52 to 0.96). Another study also showed a Norplant group also had greater weight gain (kg) than an IUD group (mean difference 1.10; 95% CI 0.36 to 1.84). We found little evidence of weight gain when using POCs. Mean gain was less than 2 kg for most studies up to 12 months, and usually similar for the comparison group using another contraceptive. Appropriate counseling about typical weight gain may help reduce discontinuation of contraceptives due to perceptions of weight gain.

Mechanisms of normal and abnormal endometrial bleeding

Expression of tissue factor (TF), the primary initiator of coagulation, is enhanced in decidualized human endometrial stromal cells (HESC) during the progesterone-dominated luteal phase. Progesterone also augments a second HESC hemostatic factor, plasminogen activator inhibitor-1 (PAI-1). In contrast, progestins inhibit HESC matrix metalloproteinase (MMP)-1, 3 and 9 expression to stabilize endometrial stromal and vascular extracellular matrix. Through these mechanisms decidualized endometrium is rendered both hemostatic and resistant to excess trophoblast invasion in the mid-luteal phase and throughout gestation to prevent hemorrhage and accreta. In non-fertile cycles, progesterone withdrawal results in decreased HESC TF and PAI-expression and increased MMP activity and inflammatory cytokine production promoting the controlled hemorrhage of menstruation and related tissue sloughing. In contrast to these well ordered biochemical processes, unpredictable endometrial bleeding associated with anovulation reflects absence of progestational effects on TF, PAI-1 and MMP activity as well as unrestrained angiogenesis rendering the endometrium non-hemostatic, proteolytic and highly vascular. Abnormal bleeding associated with long-term progestin-only contraceptives results not from impaired hemostasis but from unrestrained angiogenesis leading to large fragile endometrial vessels. This abnormal angiogenesis reflects progestational inhibition of endometrial blood flow promoting local hypoxia and generation of reactive oxygen species that increase production of angiogenic factors such as vascular endothelial growth factor (VEGF) in HESCs and Angiopoietin-2 (Ang-2) in endometrial endothelial cells while decreasing HESC expression of angiostatic, Ang-1. The resulting vessel fragility promotes bleeding. Aberrant angiogenesis also underlies abnormal bleeding associated with myomas and endometrial polyps however there are gaps in our understanding of this pathology.

P.3.012 The influence of hormone replacement therapy on the serotonin-1A receptor binding in postmenopausal women

We performed a systematic review to look for an association between progestin-only contraception and depression.We searched PubMed, Ovid and Web of Science for English-language articles including progestin-only contraception and depression from database inception to September 2016. We evaluated study quality with the procedures guiding reviews for the United States Preventive Services Task Force and the Cochrane Risk of Bias Tools. We included studies that evaluated progestin-only contraception and depression, focusing on externally validated depression measures. We excluded case studies, review articles and other psychiatric disorders.We identified 26 studies that met the inclusion criteria, including 5 randomized controlled trials, 11 cohort studies and 10 cross-sectional studies. We found minimal association between progestin-only methods and depression. No correlation with depression was found in five low-quality, high-risk-of-bias progestin subdermal implant studies and four out of five varying-quality and medium-risk-of-bias levonorgestrel intrauterine device studies. Three medroxyprogesterone acetate intramuscular injection trials with varying levels of quality and bias show no difference in depression. Two progestin-only contraceptive pill studies with varying levels of quality and bias indicate no increase in depression scores, while one good-quality, medium-bias study shows an association between progestin-only pills, the intrauterine device and depression.Despite perceptions in the community of increased depression following the initiation of progestin contraceptives, the preponderance of evidence does not support an association based on validated measures (mostly level II-1 evidence, moderate quality, low risk of bias).

Long‐term progestin‐only contraception in humans versus animal models

Abnormal uterine bleeding is the leading indication for discontinuation of long-term progestin-only contraceptives. Histological sections of endometria from long-term progestin-treated patients display abnormally enlarged blood vessels that are prone to bleed in a nonuniform manner. Because it has been complex to attain patients willing to complete long-term studies, and good quality endometrial tissues have proven difficult to obtain, animal models have been used to obviate this problem. In this review, we describe these models including the guinea pig, an animal model we have previously investigated, to assess the mechanisms involved in abnormal uterine bleeding following long-term progestin-only contraception.

Menstrual problems and contraception in women of reproductive age receiving oral anticoagulation

Background Oral anticoagulation is associated with increased bleeding complications. The aim of this study was to assess the changes in menstrual loss and pattern in women taking anticoagulant treatment. Study Design Women on oral anticoagulant (OA) treatment at the Royal Free Hospital were interviewed and completed a questionnaire about their menstrual cycle before and after commencing oral anticoagulation treatment. They were then asked to complete a pictorial bleeding assessment chart (PBAC) during their next menstrual bleeding episode. Results Fifty-three women between the ages of 20 and 50 years participated in the study. Of these, 47 women completed a PBAC. The mean duration of menstruation increased from 5 days before starting OA therapy to 7 days after the commencement of treatment. Thirty-one (66%) of the 47 women who completed the PBAC had a score that was greater than 100. The number of women who experienced flooding or clots during menstruation and intermenstrual or postcoital bleeding also increased. In total, 29 (54.7%) women changed their method of contraception during OA treatment. Seventeen women who did not want to become pregnant were not using contraception, including 10 women who were on hormonal contraception prior to starting anticoagulant therapy. Conclusion Women of reproductive age experience heavy and prolonged menstrual bleeding whilst on OA therapy. Women of reproductive age on OA therapy should be monitored for menstrual disorders to ensure that prompt and appropriate treatment is instituted. Advice about appropriate contraception should also be part of the medical care provided for these women. Barrier contraception, sterilization and progestin-only contraception are all suitable methods of contraception in this patient group.