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Endocrine Dec 2017Sex hormones play a role in bone density, cardiovascular health, and wellbeing throughout reproductive lifespan. Women with primary ovarian insufficiency (POI) have... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Sex hormones play a role in bone density, cardiovascular health, and wellbeing throughout reproductive lifespan. Women with primary ovarian insufficiency (POI) have lower estrogen levels requiring hormone therapy (HT) to manage symptoms and to protect against adverse long-term health outcomes. Yet, the effectiveness of HT in preventing adverse outcomes has not been systematically assessed. We summarize the evidence regarding effects of HT on bone and cardiovascular health in women with POI.
METHODS
A comprehensive search of the electronic databases MEDLINE, EMBASE, and Scopus was conducted by a medical reference librarian from database inception to January 2016. Randomized trials and observational cohort studies with an estrogen-based HT intervention in women with POI under the age of 40 were included. Reviewers worked independently and in duplicate to assess eligibility and risk of bias, and extract data of interest from each study.
RESULTS
The search identified 1670 articles; 12 met inclusion criteria. Four randomized clinical trials and eight cohort studies at high risk of bias enrolled 806 women with POI. The most common HT formulations were transdermal estradiol and oral conjugated equine estrogen combined with medroxyprogesterone acetate. Bone mineral density was the most frequent outcome, with three out of eight studies showing HT associated increase benefits. Only one study reported effects on fractures or vasomotor symptoms and none on cardiovascular mortality. Results regarding lipid profiles were inconsistent.
CONCLUSIONS
Evidence supporting bone and cardiovascular benefits of HT in women with POI is limited by high risk of bias, reliance on surrogate outcomes, and heterogeneity of trials regarding the formulation, dose, route of administration, and regimen of HT. Further research addressing patient important outcomes such as fractures, stroke, and cardiovascular mortality are crucial to optimize benefits of this therapy.
Topics: Adult; Estrogen Replacement Therapy; Estrogens; Female; Humans; Middle Aged; Primary Ovarian Insufficiency
PubMed: 29039146
DOI: 10.1007/s12020-017-1435-x -
BioMed Research International 2022Endometrial cancer (EC) is one of the most common gynecologic malignancy, mostly in postmenopausal women. The gold standard treatment for EC is surgery, but in the early... (Review)
Review
BACKGROUND
Endometrial cancer (EC) is one of the most common gynecologic malignancy, mostly in postmenopausal women. The gold standard treatment for EC is surgery, but in the early stages, it is possible to opt for conservative treatment. In the last decade, different clinical and pathological markers have been studied to identify women who respond to conservative treatment. A lot of immunohistochemical markers have been evaluated to predict response to progestin treatment, even if their usefulness is still unclear; the prognosis of this neoplasm depends on tumor stage, and a specific therapeutic protocol is set according to the stage of the disease.
OBJECTIVE
(1) To provide an overview of the conservative management of Stage 1A Grade (G) 2 endometrioid EC (FIGO) and the oncological and reproductive outcomes related; (2) to describe the molecular alterations before and after progestin therapy in patients undergoing conservative treatment.
MATERIALS AND METHODS
A systematic computerized search of the literature was performed in the main electronic databases (MEDLINE, Embase, Web of Science, PubMed, and Cochrane Library), from 2010 to September 2021, in order to evaluate the oncological and reproductive outcomes in patients with G2 stage IA EC who ask for fertility-sparing treatment. The expression of several immunohistochemical markers was evaluated in pretreatment phase and during the follow-up in relation to response to hormonal therapy. Only scientific publications in English were included. The risk of bias assessment was performed. Review authors' judgments were categorized as "low risk," "high risk," or "unclear risk" of bias.
RESULTS
Twelve articles were included in the study: 7 observational studies and 5 case series/reports. Eighty-four patients who took progestins (megestrol acetate, medroxyprogesterone acetate, and/or levonorgestrel-releasing intrauterine devices) were analyzed. The publication bias analysis turned out to be "low." 54/84 patients had a complete response, 23/84 patients underwent radical surgery, and 20/84 had a relapse after conservative treatment. Twenty-two patients had a pregnancy. The length of follow-up was variable, from 6 to 142 months according to the different studies analyzed. Several clinical and pathological markers have been studied to identify women who do not respond to conservative treatment: PR and ER were the most studied predictive markers, in particular PR appeared as the most promising; MMR, SPAG9, Ki67, and Nrf2-survivin pathway provided good results with a significant association with a good response to progestin therapy. However, no reliable predictive markers are currently available to be used in clinical practice.
CONCLUSIONS
The conservative treatment may be an option for patients with stage IA G2 EEC who desire to preserve their fertility. The immunohistochemical markers evaluation looks promising in predicting response to conservative treatment. Further large series and randomized clinical trials are needed to confirm these results.
Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents, Hormonal; Carcinoma, Endometrioid; Endometrial Neoplasms; Female; Fertility Preservation; Humans; Ki-67 Antigen; Levonorgestrel; Medroxyprogesterone Acetate; Megestrol Acetate; NF-E2-Related Factor 2; Neoplasm Recurrence, Local; Pregnancy; Progestins; Survivin
PubMed: 36203482
DOI: 10.1155/2022/4070368 -
The Cochrane Database of Systematic... Oct 2019Catamenial epilepsy describes a worsening of seizures in relation to the menstrual cycle and may affect around 40% of women with epilepsy. Vulnerable days of the... (Review)
Review
BACKGROUND
Catamenial epilepsy describes a worsening of seizures in relation to the menstrual cycle and may affect around 40% of women with epilepsy. Vulnerable days of the menstrual cycle for seizures are perimenstrually (C1 pattern), at ovulation (C2 pattern), and during the luteal phase (C3 pattern). A reduction in progesterone levels premenstrually and reduced secretion during the luteal phase is implicated in catamenial C1 and C3 patterns. A reduction in progesterone has been demonstrated to reduce sensitivity to the inhibitory neurotransmitter in preclinical studies, hence increasing risk of seizures. A pre-ovulatory surge in oestrogen has been implicated in the C2 pattern of seizure exacerbation, although the exact mechanism by which this surge increases risk is uncertain. Current treatment practices include the use of pulsed hormonal (e.g. progesterone) and non-hormonal treatments (e.g. clobazam or acetazolamide) in women with regular menses, and complete cessation of menstruation using synthetic hormones (e.g. medroxyprogesterone (Depo-Provera) or gonadotropin-releasing hormone (GnRH) analogues (triptorelin and goserelin)) in women with irregular menses.Catamenial epilepsy and seizure exacerbation is common in women with epilepsy, and may have a significant negative impact on quality of life. Women may not be receiving appropriate treatment for their seizures because of uncertainty regarding which treatment works best and when in the menstrual cycle treatment should be taken, as well as the possible impact on fertility, the menstrual cycle, bone health, and cardiovascular health. This review aimed to address these issues in order to inform clinical practice and future research.
OBJECTIVES
To evaluate the efficacy and tolerability of hormonal and non-hormonal treatments for seizures exacerbated by the menstrual cycle in women with regular or irregular menses. We synthesised the evidence from randomised controlled trials of hormonal and non-hormonal treatments in women with catamenial epilepsy of any pattern.
SEARCH METHODS
We searched the following databases to 10 January 2019: Cochrane Register of Studies (CRS Web; includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL)), MEDLINE (Ovid: 1946 to 9 January 2019), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies.
SELECTION CRITERIA
We included randomised and quasi-randomised controlled trials (RCTs) of blinded or opeṉlabel design that randomised participants individually (i.e. cluster-randomised trials were excluded). We included cross-over trials if each treatment period was at least 12 weeks in length and the trial had a suitable wash-out period. Types of interventions included: women with any pattern of catamenial epilepsy who received a hormonal or non-hormonal drug intervention in addition to an existing antiepileptic drug regimen for a minimum treatment duration of 12 weeks.
DATA COLLECTION AND ANALYSIS
We extracted data on study design factors and participant demographics for the included studies. The primary outcomes of interest were: proportion seizure-free, proportion of responders (at least 50% decrease in seizure frequency from baseline), and mean change in seizure frequency. Secondary outcomes included: number of withdrawals, number of women experiencing adverse events of interest (seizure exacerbation, cardiac events, thromboembolic events, osteoporosis and bone health, mood disorders, sedation, menstrual cycle disorders, and fertility issues), and quality of life outcomes.
MAIN RESULTS
We identified 62 records from the databases and search strategies. Following title, abstract, and full-text screening, we included eight full-text articles reporting on four double-blind, placebo-controlled RCTs. We included two cross-over RCTs of pulsed norethisterone and two parallel RCTs of pulsed progesterone recruiting a total of 192 women aged between 13 and 45 years with catamenial epilepsy. We found no RCTs for non-hormonal treatments of catamenial epilepsy or for women with irregular menses.Meta-analysis was not possible for the primary outcomes, therefore we undertook a narrative synthesis. For the two RCTs evaluating norethisterone versus placebo (24 participants), there were no reported treatment differences for mean change in seizure frequency. Outcomes for the proportion seizure-free and 50% responders were not reported. For the RCTs evaluating progesterone versus placebo (168 participants), the studies reported conflicting results on the primary outcomes. One progesterone RCT reported no significant difference between progesterone 600 mg/day taken on day 14 to 28 and placebo with respect to 50% responders, seizure freedom rates, and change in seizure frequency for any seizure type. The other progesterone RCT reported that the decrease in seizure frequency from baseline in the progesterone group was significantly higher than the decrease in seizure frequency from baseline in the placebo group.Results of secondary efficacy outcomes showed no significant difference in terms of treatment withdrawal for any reason in the pooled progesterone RCTs when compared to placebo (pooled risk ratio (RR) 1.56, 95% confidence interval (CI) 0.81 to 3.00, P = 0.18, I = 0%) or for treatment withdrawals due to adverse events (pooled RR 2.91, 95% CI 0.53 to 16.17, P = 0.22, I = 0%). No treatment withdrawals from the norethisterone RCTs were reported. The RCTs reported limited information on adverse events, although one progesterone RCT reported no significant difference in the number of women experiencing adverse events (diarrhoea, dyspepsia, nausea, vomiting, fatigue, nasopharyngitis, dizziness, headache, and depression). No studies reported on quality of life.We judged the evidence from the included progesterone RCTs to be of low to moderate certainty due to risk of bias and from the included norethisterone RCTs to be of very low certainty due to serious imprecision and risk of bias.
AUTHORS' CONCLUSIONS
This review provides very low-certainty evidence of no treatment difference between norethisterone and placebo, and moderate- to low-certainty evidence of no treatment difference between progesterone and placebo for catamenial epilepsy. However, as all the included studies were underpowered, important clinical effects cannot be ruled out.Our review highlighted an overall deficiency in the literature base on the effectiveness of a wide range of other hormonal and non-hormonal interventions currently being used in practice, particularly for those patients who do not have regular menses. Further clinical trials are needed in this area.
PubMed: 31608992
DOI: 10.1002/14651858.CD013225.pub2 -
American Journal of Preventive Medicine Nov 2018The objective of this systematic review was to update a prior review and summarize the evidence on the impact of family planning reminder systems (e.g., daily text...
CONTEXT
The objective of this systematic review was to update a prior review and summarize the evidence on the impact of family planning reminder systems (e.g., daily text messages reminding oral contraception users to take a pill).
EVIDENCE ACQUISITION
Multiple databases, including PubMed, were searched during 2016-2017 for articles published from March 1, 2011, to November 30, 2016, describing studies of reminder systems.
EVIDENCE SYNTHESIS
The search strategy identified 24,953 articles, of which two studies met the inclusion criteria. In total with the initial review, four studies (including two RCTs) examined reminder systems among oral contraception users, with two of three that examined correct use finding a statistically significant positive impact, and one RCT finding a positive impact on knowledge and continuation. Of three studies (including two RCTs) that examined reminder systems among depot medroxyprogesterone acetate users, one of three that examined correct use found a statistically significant positive impact on timely injections at 3 months, and one study found no effect on continued use at 12 months.
CONCLUSIONS
Although this review found mixed support for the effectiveness of reminder systems on family planning behaviors, the highest quality evidence yielded null findings related to correct use of oral contraception and timely depot medroxyprogesterone acetate injections beyond 3 months, and found positive findings related to oral contraception continuation and knowledge. Future studies would be strengthened by objectively measuring outcomes and examining additional contraceptive methods and outcomes at least 12 months post-intervention.
THEME INFORMATION
This article is part of a theme issue entitled Updating the Systematic Reviews Used to Develop the U.S. Recommendations for Providing Quality Family Planning Services, which is sponsored by the Office of Population Affairs, U.S. Department of Health and Human Services.
Topics: Contraception; Contraception Behavior; Family Planning Services; Humans; Randomized Controlled Trials as Topic; Reminder Systems; Text Messaging; United States; United States Dept. of Health and Human Services
PubMed: 30342634
DOI: 10.1016/j.amepre.2018.07.009 -
BMJ Supportive & Palliative Care Sep 2016Cachexia describes a complex pathological syndrome of muscle wasting, anorexia and weight loss. Progesterone therapies have been shown to improve appetite and promote... (Review)
Review
BACKGROUND
Cachexia describes a complex pathological syndrome of muscle wasting, anorexia and weight loss. Progesterone therapies have been shown to improve appetite and promote weight gain in patients with cachexia; however, research has focused heavily on patients with cancer, and its effectiveness in other diseases remains unclear.
AIMS
This systematic review aimed to present the evidence available for progesterone therapy as a treatment for non-cancer cachexia.
METHOD
Surrogate outcome measures used were weight change, lean body mass (LBM), muscle strength, appetite, health-related quality of life (HRQOL) and serum albumin. Both randomised and non-randomised trials were included. A literature search of clinical trials using the medical subject heading (MeSH) terms 'cachexia' OR 'anorexia' OR 'weight' OR 'frail (truncated)' OR 'appetite' OR 'wasting syndrome' PLUS 'megestrol acetate' OR 'medroxyprogesterone acetate' was performed.
RESULTS
Eighteen studies were included in this review; 12 randomised control trials and 6 non-randomised trials. This collated results from 916 patients with HIV/AIDS, end-stage renal failure, chronic obstructive pulmonary disease (COPD) and geriatric cachexia. Meta-analysis comparing progesterone therapy with placebo concluded mean change in weight was not significant (mean difference (MD) 1.56, 95% CI -0.36 to 3.52, p=0.12). There was little evidence to show significant impact on LBM, and no trials looked at muscle strength. There was a paucity of evidence looking at appetite and HRQOL; however, results were generally positive.
CONCLUSIONS
Current evidence does not support the use of progesterone therapies for non-cancer cachexia. There may however be a limited role for its use as an appetite stimulant in a palliative context on a case-by-case basis.
Topics: Body Weight; Cachexia; Humans; Progesterone; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 27098973
DOI: 10.1136/bmjspcare-2015-001041 -
Contraception Oct 2014Whether use of various types of hormonal contraception (HC) affect risk of HIV acquisition is a critical question for women's health. For this systematic review, we... (Review)
Review
Whether use of various types of hormonal contraception (HC) affect risk of HIV acquisition is a critical question for women's health. For this systematic review, we identified 22 studies published by January 15, 2014 which met inclusion criteria; we classified thirteen studies as having severe methodological limitations, and nine studies as "informative but with important limitations". Overall, data do not support an association between use of oral contraceptives and increased risk of HIV acquisition. Uncertainty persists regarding whether an association exists between depot-medroxyprogesterone acetate (DMPA) use and risk of HIV acquisition. Most studies suggested no significantly increased HIV risk with norethisterone enanthate (NET-EN) use, but when assessed in the same study, point estimates for NET-EN tended to be larger than for DMPA, though 95% confidence intervals overlapped substantially. No data have suggested significantly increased risk of HIV acquisition with use of implants, though data were limited. No data are available on the relationship between use of contraceptive patches, rings, or hormonal intrauterine devices and risk of HIV acquisition. Women choosing progestin-only injectable contraceptives such as DMPA or NET-EN should be informed of the current uncertainty regarding whether use of these methods increases risk of HIV acquisition, and like all women at risk of HIV, should be empowered to access and use condoms and other HIV preventative measures. Programs, practitioners, and women urgently need guidance on how to maximize health with respect to avoiding both unintended pregnancy and HIV given inconclusive or limited data for certain HC methods.
Topics: Administration, Oral; Africa; Condoms; Contraceptive Agents, Female; Female; HIV Infections; Humans; Injections, Intramuscular; Medroxyprogesterone Acetate; Norethindrone
PubMed: 25183264
DOI: 10.1016/j.contraception.2014.07.009 -
Contraception Dec 2016Women with depressive or bipolar disorders are at an increased risk for unintended pregnancy. (Review)
Review
BACKGROUND
Women with depressive or bipolar disorders are at an increased risk for unintended pregnancy.
OBJECTIVE
To examine the safety of hormonal contraception among women with depressive and bipolar disorders.
METHODS
We searched for articles published through January 2016 on the safety of using any hormonal contraceptive method among women with depressive or bipolar disorders, including those who had been diagnosed clinically or scored above threshold levels on a validated screening instrument. Outcomes included changes in symptoms, hospitalization, suicide and modifications in medication regimens such as increase or decrease in dosage or changes in type of drug.
RESULTS
Of 2376 articles, 6 met the inclusion criteria. Of three studies that examined women clinically diagnosed with depressive or bipolar disorder, one found that oral contraceptives (OCs) did not significantly change mood across the menstrual cycle among women with bipolar disorder, whereas mood did significantly change across the menstrual cycle among women not using OCs; one found no significant differences in the frequency of psychiatric hospitalizations among women with bipolar disorder who used depot medroxyprogesterone acetate (DMPA), intrauterine devices (IUDs) or sterilization; and one found no increase in depression scale scores among women with depression using and not using OCs, for both those treated with fluoxetine and those receiving placebo. Of three studies that examined women who met a threshold for depression on a screening instrument, one found that adolescent girls using combined OCs (COCs) had significantly improved depression scores after 3 months compared with placebo, one found that OC users had similar odds of no longer being depressed at follow-up compared with nonusers, and one found that COC users were less frequently classified as depressed over 11 months than IUD users.
CONCLUSIONS
Limited evidence from six studies found that OC, levonorgestrel-releasing IUD and DMPA use among women with depressive or bipolar disorders was not associated with worse clinical course of disease compared with no hormonal method use.
Topics: Bipolar Disorder; Contraceptives, Oral; Depressive Disorder; Equipment Safety; Female; Humans; Intrauterine Devices, Copper; Levonorgestrel; Medroxyprogesterone Acetate; Pregnancy; Pregnancy, Unplanned; Psychiatric Status Rating Scales; Risk Assessment
PubMed: 27364100
DOI: 10.1016/j.contraception.2016.06.012 -
The Cochrane Database of Systematic... Aug 2019Heavy menstrual bleeding (HMB) is a menstrual blood loss perceived by women as excessive that affects the health of women of reproductive age, interfering with their...
BACKGROUND
Heavy menstrual bleeding (HMB) is a menstrual blood loss perceived by women as excessive that affects the health of women of reproductive age, interfering with their physical, emotional, social and material quality of life. Whilst abnormal menstrual bleeding may be associated with underlying pathology, in the present context, HMB is defined as excessive menstrual bleeding in the absence of other systemic or gynaecological disease. The first-line therapy is usually medical, avoiding possibly unnecessary surgery. Of the wide variety of medications used to reduce HMB, oral progestogens were originally the most commonly prescribed agents. This review assesses the effectiveness of two different types and regimens of oral progestogens in reducing ovulatory HMB.This is the update of a Cochrane review last updated in 2007, and originally named "Effectiveness of cyclical progestagen therapy in reducing heavy menstrual bleeding" (1998).
OBJECTIVES
To determine the effectiveness, safety and tolerability of oral progestogen therapy taken either during the luteal phase (short cycle) or for a longer course of 21 days per cycle (long cycle), in achieving a reduction in menstrual blood loss in women of reproductive age with HMB.
SEARCH METHODS
In January 2019 we searched Cochrane Gynaecology and Fertility's specialized register, CENTRAL, MEDLINE, Embase, CINAHL and PsycInfo. We also searched trials registers, other sources of unpublished or grey literature and reference lists of retrieved trials. We also checked citation lists of review articles to identify trials.
SELECTION CRITERIA
Randomized controlled trials (RCTs) comparing different treatments for HMB that included cyclical oral progestogens were eligible.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials for inclusion, assessed trials for risk of bias and extracted data. We contacted trial authors for clarification of methods or additional data when necessary. We only assessed adverse events if they were separately measured in the included trials. We compared cyclical oral progestogen in different regimens and placebo or other treatments. Our primary outcomes were menstrual blood loss and satisfaction with treatment; the secondary outcomes were number of days of bleeding, quality of life, compliance and acceptability of treatment, adverse events and costs.
MAIN RESULTS
This review identified 15 randomized controlled trials (RCTs) with 1071 women in total. Most of the women knew which treatment they were receiving, which may have influenced their judgements about menstrual blood loss and satisfaction. Other aspects of trial quality varied among trials.We did not identify any RCTs comparing progestogen treatment with placebo. We assessed comparisons between oral progestogens and other medical therapies separately according to different regimens.Short-cycle progestogen therapy during the luteal phase (medroxyprogesterone acetate or norethisterone for 7 to 10 days, from day 15 to 19) was inferior to other medical therapy, including tranexamic acid, danazol and the progestogen-releasing intrauterine system (Pg-IUS (off of the market since 2001)), releasing 60 mcg of progesterone daily, with respect to reduction of menstrual blood loss (mean difference (MD) 37.29, 95% confidence interval (CI) 17.67 to 56.91; I = 50%; 6 trials, 145 women). The rate of satisfaction and the quality of life with treatment was similar in both groups. The number of bleeding days was greater on the short cycle progestogen group compared to other medical treatments. Adverse events (such as gastrointestinal symptoms and weight gain) were more likely with danazol when compared with progestogen treatment. We note that danazol is no longer in general use for treating HMB.Long-cycle progestogen therapy (medroxyprogesterone acetate or norethisterone), from day 5 to day 26 of the menstrual cycle, is also inferior to the levonorgestrel-releasing intrauterine system (LNG-IUS), releasing tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss (MD 16.88, 95% CI 10.93 to 22.84; I = 87%; 4 trials, 355 women). A higher proportion of women taking norethisterone found their treatment unacceptable compared to women having Pg-IUS (Peto odds ratio (OR) 0.12, 95% CI 0.03 to 0.40; 1 trial, 40 women). However, the adverse effects of breast tenderness and intermenstrual bleeding were more likely in women with the LNG-IUS. No trials reported on days of bleeding or quality of life for this comparison.The evidence supporting these findings was limited by low or very low gradings of quality; thus, we are uncertain about the findings and there is a potential that they may change if we identify other trials.
AUTHORS' CONCLUSIONS
Low- or very low-quality evidence suggests that short-course progestogen was inferior to other medical therapy, including tranexamic acid, danazol and the Pg-IUS with respect to reduction of menstrual blood loss. Long cycle progestogen therapy (medroxyprogesterone acetate or norethisterone) was also inferior to the LNG-IUS, tranexamic acid and ormeloxifene, but may be similar to the combined vaginal ring with respect to reduction of menstrual blood loss.
Topics: Danazol; Female; Humans; Intrauterine Devices, Medicated; Medroxyprogesterone Acetate; Menorrhagia; Progesterone; Progestins; Quality of Life; Randomized Controlled Trials as Topic; Tranexamic Acid
PubMed: 31425626
DOI: 10.1002/14651858.CD001016.pub3 -
The Cochrane Database of Systematic... Jul 2015Age-related decline in bone mass increases the risk of skeletal fractures, especially those of the hip, spine, and wrist. Steroidal contraceptives have been associated... (Review)
Review
BACKGROUND
Age-related decline in bone mass increases the risk of skeletal fractures, especially those of the hip, spine, and wrist. Steroidal contraceptives have been associated with changes in bone mineral density in women. Whether such changes affect the risk of fractures later in life is unclear. Hormonal contraceptives are among the most effective and most widely-used contraceptives. Concern about fractures may limit the use of these effective contraceptives. Observational studies can collect data on premenopausal contraceptive use as well as fracture incidence later in life.
OBJECTIVES
We systematically reviewed the evidence from observational studies of hormonal contraceptive use for contraception and the risk of fracture in women.
SEARCH METHODS
Through June 2015, we searched for observational studies. The databases included PubMed, POPLINE, Cochrane Central Register of Controlled Trials (CENTRAL), LILACS, EMBASE, CINAHL, and Web of Science. We also searched for recent clinical trials through ClinicalTrials.gov and the ICTRP. For other studies, we examined reference lists of relevant articles and wrote to investigators for additional reports.
SELECTION CRITERIA
We included cohort and case-control studies of hormonal contraceptive use. Interventions included comparisons of a hormonal contraceptive with a non-hormonal contraceptive, no contraceptive, or another hormonal contraceptive. The primary outcome was the risk of fracture.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted the data. One author entered the data into RevMan, and a second author verified accuracy. We examined the quality of evidence using the Newcastle-Ottawa Quality Assessment Scale (NOS), developed for case-control and cohort studies. Sensitivity analysis included studies of moderate or high quality based on our assessment with the NOS.Given the need to control for confounding factors in observational studies, we used adjusted estimates from the models as reported by the authors. Where we did not have adjusted analyses, we calculated the odds ratio (OR) with 95% confidence interval (CI). Due to varied study designs, we did not conduct meta-analysis.
MAIN RESULTS
We included 14 studies (7 case-control and 7 cohort studies). These examined oral contraceptives (OCs), depot medroxyprogesterone acetate (DMPA), and the hormonal intrauterine device (IUD). This section focuses on the sensitivity analysis with six studies that provided moderate or high quality evidence.All six studies examined oral contraceptive use. We noted few associations with fracture risk. One cohort study reported OC ever-users had increased risk for all fractures (RR 1.20, 95% CI 1.08 to 1.34). However, a case-control study with later data from a subset reported no association except for those with 10 years or more since use (OR 1.55, 95% CI 1.03 to 2.33). Another case-control study reported increased risk only for those who had 10 or more prescriptions (OR 1.09, 95% CI 1.03 to 1.16). A cohort study of postmenopausal women found no increased fracture risk for OC use after excluding women with prior fracture. Two other studies found little evidence of association between OC use and fracture risk. A cohort study noted increased risk for subgroups, such as those with longer use or specific intervals since use. A case-control study reported increased risk for any fracture only among young women with less than average use.Two case-control studies also examined progestin-only contraceptives. One reported increased fracture risk for DMPA ever-use (OR 1.44, 95% CI 1.01 to 2.06), more than four years of use (OR 2.16, 95% CI 1.32 to 3.53), and women over 50 years old. The other reported increased risk for any past use, including one or two prescriptions (OR 1.17, 95% CI 1.07 to 1.29) and for current use of 3 to 9 prescriptions (OR 1.36, 95% CI 1.15 to 1.60) or 10 or more (OR 1.54, 95% CI 1.33 to 1.78). For the levonorgestrel-releasing IUD, one study reported reduced fracture risk for ever-use (OR 0.75, 95% CI 0.64 to 0.87) and for longer use.
AUTHORS' CONCLUSIONS
Observational studies do not indicate an overall association between oral contraceptive use and fracture risk. Some reported increased risk for specific user subgroups. DMPA users may have an increased fracture risk. One study indicated hormonal IUD use may be associated with decreased risk. Observational studies need adjusted analysis because the comparison groups usually differ. Investigators should be clear about the variables examined in multivariate analysis.
Topics: Age Factors; Case-Control Studies; Cohort Studies; Contraceptives, Oral, Hormonal; Female; Fractures, Bone; Humans; Intrauterine Devices, Medicated; Medroxyprogesterone Acetate; Observational Studies as Topic; Progestins; Time Factors
PubMed: 26195091
DOI: 10.1002/14651858.CD009849.pub3 -
The Cochrane Database of Systematic... Feb 2015Sexual offending is a serious social problem, a public health issue, and a major challenge for social policy. Victim surveys indicate high incidence and prevalence... (Review)
Review
BACKGROUND
Sexual offending is a serious social problem, a public health issue, and a major challenge for social policy. Victim surveys indicate high incidence and prevalence levels and it is accepted that there is a high proportion of hidden sexual victimisation. Surveys report high levels of psychiatric morbidity in survivors of sexual offences.Biological treatments of sex offenders include antilibidinal medication, comprising hormonal drugs that have a testosterone-suppressing effect, and non-hormonal drugs that affect libido through other mechanisms. The three main classes of testosterone-suppressing drugs in current use are progestogens, antiandrogens, and gonadotropin-releasing hormone (GnRH) analogues. Medications that affect libido through other means include antipsychotics and serotonergic antidepressants (SSRIs).
OBJECTIVES
To evaluate the effects of pharmacological interventions on target sexual behaviour for people who have been convicted or are at risk of sexual offending.
SEARCH METHODS
We searched CENTRAL (2014, Issue 7), Ovid MEDLINE, EMBASE, and 15 other databases in July 2014. We also searched two trials registers and requested details of unidentified, unpublished, or ongoing studies from investigators and other experts.
SELECTION CRITERIA
Prospective controlled trials of antilibidinal medications taken by individuals for the purpose of preventing sexual offences, where the comparator group received a placebo, no treatment, or 'standard care', including psychological treatment.
DATA COLLECTION AND ANALYSIS
Pairs of authors, working independently, selected studies, extracted data, and assessed the risk of bias of included studies. We contacted study authors for additional information, including details of methods and outcome data.
MAIN RESULTS
We included seven studies with a total of 138 participants, with data available for 123. Sample sizes ranged from 9 to 37. Judgements for categories of risk of bias varied: concerns were greatest regarding allocation concealment, blinding of outcome assessors, and incomplete outcome data (dropout rates in the five community-based studies ranged from 3% to 54% and results were usually analysed on a per protocol basis).Participant characteristics in the seven studies were heterogeneous, but the vast majority had convictions for sexual offences, ranging from exhibitionism to rape and child molestation.Six studies examined the effectiveness of three testosterone-suppressing drugs: cyproterone acetate (CPA), ethinyl oestradiol (EO), and medroxyprogesterone acetate (MPA); a seventh evaluated two antipsychotics (benperidol and chlorpromazine). Five studies were placebo-controlled; in two, MPA was administered as an adjunctive treatment to a psychological therapy (assertiveness training or imaginal desensitisation). Meta-analysis was not possible due to heterogeneity of interventions, comparators, study designs, and other issues. The quality of the evidence overall was poor. In addition to methodological issues, much evidence was indirect.
PRIMARY OUTCOME
recividism. Two studies reported recidivism rates formally. One trial of intramuscular MPA plus imaginal desensitisation (ID) found no reports of recividism at two-year follow-up for the intervention group (n = 10 versus one relapse within the group treated by ID alone). A three-armed trial of oral MPA, alone or in combination with psychological treatment, reported a 20% rate of recidivism amongst those in the combined treatment arm (n = 15) and 50% of those in the psychological treatment only group (n = 12). Notably, all those in the 'oral MPA only' arm of this study (n = 5) dropped out immediately, despite treatment being court mandated.Two studies did not report recidivism rates as they both took place in one secure psychiatric facility from which no participant was discharged during the study, whilst another three studies did not appear directly to measure recividism but rather abnormal sexual activity alone.
SECONDARY OUTCOMES
The included studies report a variety of secondary outcomes. Results suggest that the frequency of self reported deviant sexual fantasies may be reduced by testosterone-suppressing drugs, but not the deviancy itself (three studies). Where measured, hormonal levels, particularly levels of testosterone, tended to correlate with measures of sexual activity and with anxiety (two studies). One study measured anxiety formally; one study measured anger or aggression. Adverse events: Six studies provided information on adverse events. No study tested the effects of testosterone-suppressing drugs beyond six to eight months and the cross-over design of some studies may obscure matters (given the 'rebound effect' of some hormonal treatments). Considerable weight gain was reported in two trials of oral MPA and CPA. Side effects of intramuscular MPA led to discontinuation in some participants after three to five injections (the nature of these side effects was not described). Notable increases in depression and excess salivation were reported in one trial of oral MPA. The most severe side effects (extra-pyramidal movement disorders and drowsiness) were reported in a trial of antipsychotic medication for the 12 participants in the study. No deaths or suicide attempts were reported in any study. The latter is important given the association between antilibidinal hormonal medication and mood changes.
AUTHORS' CONCLUSIONS
We found only seven small trials (all published more than 20 years ago) that examined the effects of a limited number of drugs. Investigators reported issues around acceptance and adherence to treatment. We found no studies of the newer drugs currently in use, particularly SSRIs or GnRH analogues. Although there were some encouraging findings in this review, their limitations do not allow firm conclusions to be drawn regarding pharmacological intervention as an effective intervention for reducing sexual offending.The tolerability, even of the testosterone-suppressing drugs, was uncertain given that all studies were small (and therefore underpowered to assess adverse effects) and of limited duration, which is not consistent with current routine clinical practice. Further research is required before it is demonstrated that their administration reduces sexual recidivism and that tolerability is maintained.It is a concern that, despite treatment being mandated in many jurisdictions, evidence for the effectiveness of pharmacological interventions is so sparse and that no RCTs appear to have been published in two decades. New studies are therefore needed and should include trials with larger sample sizes, of longer duration, evaluating newer medications, and with results stratified according to category of sexual offenders. It is important that data are collected on the characteristics of those who refuse and those who drop out, as well as those who complete treatment.
Topics: Adolescent; Adult; Aged; Androgen Antagonists; Antipsychotic Agents; Child; Child Abuse, Sexual; Desensitization, Psychologic; Exhibitionism; Humans; Libido; Male; Middle Aged; Randomized Controlled Trials as Topic; Rape; Recurrence; Sex Offenses; Sexual Behavior
PubMed: 25692326
DOI: 10.1002/14651858.CD007989.pub2