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Menopause (New York, N.Y.) Dec 2023Use of menopausal hormone therapy (HT) fell precipitously after 2002, largely as a result of the Women's Health Initiative's report claiming that the combination of... (Review)
Review
Use of menopausal hormone therapy (HT) fell precipitously after 2002, largely as a result of the Women's Health Initiative's report claiming that the combination of conjugated equine estrogen (CEE) and medroxyprogesterone acetate increased breast cancer risk and did not improve quality of life. More recently, Women's Health Initiative (WHI) publications acknowledge HT as the most effective treatment for managing menopausal vasomotor symptoms and report that CEE alone reduces the risk of breast cancer by 23% while reducing breast cancer death by 40%. Their sole remaining concern is a small increase in breast cancer incidence with CEE and medroxyprogesterone acetate (1 per 1,000 women per year) but with no increased risk of breast cancer mortality. This article closely examines evidence that calls even this claim of breast cancer risk into serious question, including the WHI's reporting of nonsignificant results as if they were meaningful, a misinterpretation of its own data, and the misleading assertion that the WHI's findings have reduced the incidence of breast cancer in the United States. A generation of women has been deprived of HT largely as a result of this widely publicized misinterpretation of the data. This article attempts to rectify this misunderstanding, with the goal of helping patients and physicians make informed joint decisions about the use of HT.
Topics: Female; Humans; United States; Breast Neoplasms; Medroxyprogesterone Acetate; Quality of Life; Women's Health; Estrogens, Conjugated (USP); Menopause; Estrogen Replacement Therapy
PubMed: 37847875
DOI: 10.1097/GME.0000000000002267 -
CMAJ : Canadian Medical Association... Aug 2021
Topics: Adolescent; Bone Density; Canada; Contraception; Contraceptive Agents, Female; Desogestrel; Female; Humans; Intrauterine Devices, Copper; Levonorgestrel; Long-Acting Reversible Contraception; Medroxyprogesterone Acetate; Pregnancy; Pregnancy, Unplanned; Sexually Transmitted Diseases
PubMed: 34373270
DOI: 10.1503/cmaj.202413 -
JAMA Jul 2020The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials. (Randomized Controlled Trial)
Randomized Controlled Trial
Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials.
IMPORTANCE
The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.
OBJECTIVE
To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials.
DESIGN, SETTING, AND PARTICIPANTS
Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27 347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.
INTERVENTIONS
In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration.
MAIN OUTCOMES AND MEASURES
The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.
RESULTS
Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P = .005) and was associated with statistically significantly lower breast cancer mortality with 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P = .04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P < .001) and no significant difference in breast cancer mortality with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%; HR, 1.35; 95% CI, 0.94-1.95; P= .11).
CONCLUSIONS AND RELEVANCE
In this long-term follow-up study of 2 randomized trials, prior randomized use of CEE alone, compared with placebo, among women who had a previous hysterectomy, was significantly associated with lower breast cancer incidence and lower breast cancer mortality, whereas prior randomized use of CEE plus MPA, compared with placebo, among women who had an intact uterus, was significantly associated with a higher breast cancer incidence but no significant difference in breast cancer mortality.
Topics: Aged; Breast Neoplasms; Estrogens, Conjugated (USP); Female; Follow-Up Studies; Hormone Replacement Therapy; Humans; Hysterectomy; Incidence; Medroxyprogesterone Acetate; Middle Aged; Postmenopause; Risk
PubMed: 32721007
DOI: 10.1001/jama.2020.9482 -
JAMA May 2024Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects... (Review)
Review
IMPORTANCE
Approximately 55 million people in the US and approximately 1.1 billion people worldwide are postmenopausal women. To inform clinical practice about the health effects of menopausal hormone therapy, calcium plus vitamin D supplementation, and a low-fat dietary pattern, the Women's Health Initiative (WHI) enrolled 161 808 postmenopausal US women (N = 68 132 in the clinical trials) aged 50 to 79 years at baseline from 1993 to 1998, and followed them up for up to 20 years.
OBSERVATIONS
The WHI clinical trial results do not support hormone therapy with oral conjugated equine estrogens plus medroxyprogesterone acetate for postmenopausal women or conjugated equine estrogens alone for those with prior hysterectomy to prevent cardiovascular disease, dementia, or other chronic diseases. However, hormone therapy is effective for treating moderate to severe vasomotor and other menopausal symptoms. These benefits of hormone therapy in early menopause, combined with lower rates of adverse effects of hormone therapy in early compared with later menopause, support initiation of hormone therapy before age 60 years for women without contraindications to hormone therapy who have bothersome menopausal symptoms. The WHI results do not support routinely recommending calcium plus vitamin D supplementation for fracture prevention in all postmenopausal women. However, calcium and vitamin D are appropriate for women who do not meet national guidelines for recommended intakes of these nutrients through diet. A low-fat dietary pattern with increased fruit, vegetable, and grain consumption did not prevent the primary outcomes of breast or colorectal cancer but was associated with lower rates of the secondary outcome of breast cancer mortality during long-term follow-up.
CONCLUSIONS AND RELEVANCE
For postmenopausal women, the WHI randomized clinical trials do not support menopausal hormone therapy to prevent cardiovascular disease or other chronic diseases. Menopausal hormone therapy is appropriate to treat bothersome vasomotor symptoms among women in early menopause, without contraindications, who are interested in taking hormone therapy. The WHI evidence does not support routine supplementation with calcium plus vitamin D for menopausal women to prevent fractures or a low-fat diet with increased fruits, vegetables, and grains to prevent breast or colorectal cancer. A potential role of a low-fat dietary pattern in reducing breast cancer mortality, a secondary outcome, warrants further study.
Topics: Aged; Female; Humans; Middle Aged; Breast Neoplasms; Calcium; Calcium, Dietary; Cardiovascular Diseases; Diet, Fat-Restricted; Dietary Supplements; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Hot Flashes; Medroxyprogesterone Acetate; Osteoporosis, Postmenopausal; Postmenopause; Randomized Controlled Trials as Topic; Vitamin D; Women's Health; United States
PubMed: 38691368
DOI: 10.1001/jama.2024.6542 -
Climacteric : the Journal of the... Aug 2018Progesterone is a neurosteroid and a neuroactive steroid, produced primarily by the corpus luteum and the placenta. In some animal models, progesterone affects cognitive... (Review)
Review
Progesterone is a neurosteroid and a neuroactive steroid, produced primarily by the corpus luteum and the placenta. In some animal models, progesterone affects cognitive performance, and its potential role in human cognition is especially germane to women. This role can be investigated through associations between peripheral concentrations of progesterone in blood or saliva and neuropsychological test results, through differences in cognitive profiles between women using menopausal hormone therapy with and without a progestogen, and through clinical trials. In naturally cycling reproductive-age women and pregnant women, there is no consistent relation between progesterone levels and cognition. In postmenopausal women within 6 years of menopause and not using hormone therapy, progesterone levels are positively associated with verbal memory and global cognition, but reported associations in older postmenopausal women are null. Some observational studies of postmenopausal women using hormone therapy raise concern of a small deleterious cognitive effect of progestogen (medroxyprogesterone acetate was most often reported in these studies), but this association may due to confounding factors. Small, short-term clinical trials of progesterone show no meaningful effect on cognition. The quality of evidence is low, but overall findings do not reveal consistent, clinically important effects of progesterone on cognitive function in women.
Topics: Animals; Cognition; Cognition Disorders; Estrogen Replacement Therapy; Female; Humans; Medroxyprogesterone Acetate; Memory; Neuropsychological Tests; Postmenopause; Pregnancy; Progesterone; Progestins; Randomized Controlled Trials as Topic
PubMed: 29852783
DOI: 10.1080/13697137.2018.1476484 -
International Journal of Gynaecology... Oct 2023To assess the associations between depot medroxyprogesterone acetate (DMPA) and endometrial cancer.
OBJECTIVE
To assess the associations between depot medroxyprogesterone acetate (DMPA) and endometrial cancer.
METHODS
This multicenter case-control study was conducted among tertiary hospitals in Thailand. Patients were women with endometrial cancer. Controls were women admitted for other conditions, matched for age within 5 years of the patients' age. The controls had to have no abnormal vaginal bleeding, history of hysterectomy, or cancers of the other organs. A standardized questionnaire was used to gather information. Conditional logistic regression was applied to calculate adjusted odds ratio (aORs) and 95% confidence intervals (CIs).
RESULTS
During 2015 to 2021, 378 patients and 1134 controls were included. Ever use of DMPA was associated with a 70% decreased overall risk of endometrial cancer (aOR, 0.30 [95% CI, 0.21-0.42]). Endometrial cancer risk declined by 3% (aOR, 0.97 [95% CI, 0.96-0.98]) for every 3 months of DMPA use. The magnitude of the decline in endometrial cancer risk did not vary appreciably by cancer subtypes (aOR, 0.26 [95% CI, 0.17-0.41] and 0.38 [95% CI, 0.22-0.65] for low-grade and high-grade tumors, respectively).
CONCLUSIONS
Depot medroxyprogesterone acetate use was inversely associated with endometrial cancer risk in a duration-dependent manner. This association was independent of cancer subtype.
Topics: Humans; Female; Child, Preschool; Male; Medroxyprogesterone Acetate; Case-Control Studies; Endometrial Neoplasms; Contraceptive Agents, Female; Endometrium; Delayed-Action Preparations
PubMed: 37183712
DOI: 10.1002/ijgo.14846 -
Steroids Nov 2022Quantification of serum progestin levels in clinical contraceptive studies is now routinely performed to understand progestin pharmacokinetics and to correct for... (Review)
Review
Quantification of serum progestin levels in clinical contraceptive studies is now routinely performed to understand progestin pharmacokinetics and to correct for unreliable self-reporting of contraceptive use by study participants. Many such studies are focussed on the three-monthly progestin-only intramuscular (IM) injectable contraceptive depot medroxyprogesterone acetate (DMPA-IM). Methods commonly used to measure serum MPA levels include liquid chromatography coupled to mass spectrometry (LC/MS) and radioimmunoassay (RIA); however, RIA methods have not been used in recent years. We review the available literature and find that these methods vary widely in terms of use of organic solvent extraction, use of derivitization and choice of organic solvent and chromatography columns. There is a lack of standardization of LC/MS methodology, including a lack of detailed extraction protocols. Limited evidence suggests that RIA, without organic solvent extraction, likely over-estimates progestin levels. Maximum MPA concentrations in the first two weeks post-injection show wide inter-individual and inter-study variation, regardless of quantification method used. Standardization of quantification methods and sampling time post-injection is required to improve interpretation of clinical data, in particular the side effects arising at different times depending on the pharmacokinetic profile unique to injectable contraceptives.
Topics: Contraceptive Agents; Contraceptive Agents, Female; Female; Humans; Medroxyprogesterone Acetate; Progestins; Radioimmunoassay; Solvents
PubMed: 35964796
DOI: 10.1016/j.steroids.2022.109100 -
Clinical Obstetrics and Gynecology Dec 2015Postpartum contraception is important to lengthening birth intervals and improving the health of women and children. For breastfeeding women the choice and timing of... (Review)
Review
Postpartum contraception is important to lengthening birth intervals and improving the health of women and children. For breastfeeding women the choice and timing of contraception may influence breastfeeding and infant growth patterns. Nonhormonal methods of contraception are the preferred choice for breastfeeding women. Progestin-only methods comprise a viable next option. Combined hormonal methods of contraception containing estrogen and progestin may be considered as a third option for birth control in breastfeeding women. The objective of this chapter is to review the current literature and recommendations for the use of hormonal and nonhormonal methods of contraception while breastfeeding.
Topics: Amenorrhea; Breast Feeding; Contraception; Contraception, Postcoital; Contraceptives, Oral; Drug Implants; Female; Humans; Intrauterine Devices, Medicated; Lactation; Levonorgestrel; Medroxyprogesterone Acetate; Postpartum Period; Progesterone; Progestins; Time Factors
PubMed: 26457854
DOI: 10.1097/GRF.0000000000000157 -
BMJ (Clinical Research Ed.) Jan 2019To assess the association between risk of venous thromboembolism and use of different types of hormone replacement therapy. (Comparative Study)
Comparative Study Observational Study
OBJECTIVE
To assess the association between risk of venous thromboembolism and use of different types of hormone replacement therapy.
DESIGN
Two nested case-control studies.
SETTING
UK general practices contributing to the QResearch or Clinical Practice Research Datalink (CPRD) databases, and linked to hospital, mortality, and social deprivation data.
PARTICIPANTS
80 396 women aged 40-79 with a primary diagnosis of venous thromboembolism between 1998 and 2017, matched by age, general practice, and index date to 391 494 female controls.
MAIN OUTCOME MEASURES
Venous thromboembolism recorded on general practice, mortality, or hospital records. Odds ratios were adjusted for demographics, smoking status, alcohol consumption, comorbidities, recent medical events, and other prescribed drugs.
RESULTS
Overall, 5795 (7.2%) women who had venous thromboembolism and 21 670 (5.5%) controls had been exposed to hormone replacement therapy within 90 days before the index date. Of these two groups, 4915 (85%)and 16 938 (78%) women used oral therapy, respectively, which was associated with a significantly increased risk of venous thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81). Estradiol had a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal preparations were not associated with risk of venous thromboembolism, which was consistent for different regimens (overall adjusted odds ratio 0.93, 95% confidence interval 0.87 to 1.01).
CONCLUSIONS
In the present study, transdermal treatment was the safest type of hormone replacement therapy when risk of venous thromboembolism was assessed. Transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations.
Topics: Administration, Cutaneous; Adult; Aged; Case-Control Studies; Estrogens; Female; Hormone Replacement Therapy; Humans; Medroxyprogesterone Acetate; Menopause; Middle Aged; Randomized Controlled Trials as Topic; Risk Factors; United Kingdom; Venous Thromboembolism
PubMed: 30626577
DOI: 10.1136/bmj.k4810 -
Current Opinion in Obstetrics &... Dec 2019To provide an overview of recent research and guidelines regarding contraception and breastfeeding. (Review)
Review
PURPOSE OF REVIEW
To provide an overview of recent research and guidelines regarding contraception and breastfeeding.
RECENT FINDINGS
Recent studies assessed lactogenesis, breastfeeding rates, and milk supply concerns in patients starting postpartum hormonal contraception. One study showed a small but statistically significant increase in milk supply concerns between users and nonusers of postpartum hormonal contraception. Mean time to lactogenesis and breastfeeding rates were similar between patients with immediate and delayed insertion of the levonorgestrel (LNG) implant in one study and the LNG intrauterine device (IUD) in another study. Two studies assessed nursing knowledge and attitudes toward postpartum contraception in breastfeeding women, showing that postpartum nurses had incorrect knowledge of contraceptive safety in this patient population. Both studies demonstrated persistent erroneous beliefs that depot medroxyprogesterone acetate (DMPA) adversely affects breastfeeding. In postpartum patients intending to breastfeed, more than half intended to initiate contraception within 6 weeks postpartum and few indicated effect on breastfeeding as a factor in their decision.
SUMMARY
There are no significant differences in lactogenesis, breastfeeding, and infant growth parameters between immediate postpartum (IPP) and delayed insertion of LNG implants and IUDs. Labor and delivery and postpartum nurses have persistent erroneous beliefs that DMPA negatively affects breastfeeding. Patients desire to use contraception postpartum but prenatal counseling rates and practices are of variable content and quality.
Topics: Breast Feeding; Contraception; Contraceptive Agents; Delayed-Action Preparations; Female; Gynecology; Health Knowledge, Attitudes, Practice; Hormonal Contraception; Humans; Infant; Infant, Newborn; Intrauterine Devices; Lactation; Levonorgestrel; Medroxyprogesterone Acetate; Milk, Human; Postpartum Period; Practice Guidelines as Topic; Pregnancy
PubMed: 31436540
DOI: 10.1097/GCO.0000000000000571