Conjugated equine estrogen and medroxyprogesterone acetate are associated with decreased risk of breast cancer relative to bioidentical hormone therapy and controls.

OBJECTIVE: By the 1990s it became popular for women to use hormone therapy (HT) to ease menopause symptoms. Bioidentical estrogen and progesterone are supplements whose molecular structures are identical to what is made in the human body, while synthetic supplements are ones whose structures are not. After the Women's Health Initiative found that the combined use of the synthetics conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) increased breast cancer risk, prescriptions for synthetic HT declined considerably. Since then there has been an increased interest in bioidentical HT; today there are a plethora of websites touting their benefits. However, no peer-reviewed articles support these claims. We performed a retrospective study with the objective of verifying the hypothesis that bioidentical HT is associated with decreased breast cancer risk than CEE & MPA. METHODS: We searched The Northwestern Medicine Enterprise Data Warehouse for women who initiated HT use after age 50. Women who did not take any HT drug after age 50 served as controls. Nine HT protocols were investigated for breast cancer risk. RESULTS: Significant results include CEE Alone is associated with decreased breast cancer risk (HR = 0.31), Other Synthetic Estrogen Alone is associated with increased breast cancer risk (HR = 1.49), Bioidentical Estrogen Alone is associated with decreased breast cancer risk(HR = 0.65), CEE & MPA is associated with reduced breast cancer risk (HR = 0.43), and CEE & MPA is associated with reduced breast cancer risk relative to Bioidentical Estrogen & Progesterone (HR = 0.25). DISCUSSION: Our results indicate CEE & MPA is superior to bioidentical HT as far as breast cancer risk. Furthermore, this combination is associated with decrease of breast cancer risk, contrary to previous findings. Additional retrospective studies are needed to confirm our results.

Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials.

Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality. Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials. Design, Setting, and Participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014. Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median). Main Outcomes and Measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization. Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials. Conclusions and Relevance: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years. Trial Registration: clinicaltrials.gov Identifier: NCT00000611.

The Contribution of Cervicovaginal Infections to the Immunomodulatory Effects of Hormonal Contraception.

UNLABELLED: Particular types of hormonal contraceptives (HCs) and genital tract infections have been independently associated with risk of HIV-1 acquisition. We examined whether immunity in women using injectable depot medroxyprogesterone acetate (DMPA), combined oral contraceptives (COC), or no HCs differs by the presence of cervicovaginal infections. Immune mediators were quantified in cervical swabs from 832 HIV-uninfected reproductive-age Ugandans and Zimbabweans. Bacterial infections and HIV were diagnosed by PCR, genital herpes serostatus by enzyme-linked immunosorbent assay (ELISA), altered microflora by Nugent score, and Trichomonas vaginalis and Candida albicans infection by wet mount. Generalized linear models utilizing Box-Cox-Power transformation examined associations between levels of mediators, infection status, and HCs. In no-HC users, T. vaginalis was associated with broadest spectrum of aberrant immunity (higher interleukin 1ß [IL-1ß], IL-8, macrophage inflammatory protein 3α [MIP-3α], ß-defensin 2 [BD2], and IL-1 receptor antigen [IL-1RA]). In women with a normal Nugent score and no genital infection, compared to the no-HC group, COC users showed higher levels of IL-1ß, IL-6, IL-8, and IL-1RA, while DMPA users showed higher levels of RANTES and lower levels of BD2, both associated with HIV seroconversion. These effects of COC were blunted in the presence of gonorrhea, chlamydia, trichomoniasis, candidiasis, and an abnormal Nugent score; however, RANTES was increased among COC users with herpes, chlamydia, and abnormal Nugent scores. The effect of DMPA was exacerbated by lower levels of IL-1RA in gonorrhea, chlamydia, or herpes, SLPI in gonorrhea, and IL-1ß, MIP-3α, and IL-1RA/IL1ß ratio in trichomoniasis. Thus, the effects of HC on cervical immunity depend on the genital tract microenvironment, and a weakened mucosal barrier against HIV may be a combined resultant of genital tract infections and HC use. IMPORTANCE: In this article, we show that in young reproductive-age women most vulnerable to HIV, hormonal contraceptives are associated with altered cervical immunity in a manner dependent on the presence of genital tract infections. Through altered immunity, hormones may predispose women to bacterial and viral pathogens; conversely, a preexisting specific infection or disturbed vaginal microbiota may suppress the immune activation by levonorgestrel or exacerbate the suppressed immunity by DMPA, thus increasing HIV risk by their cumulative action. Clinical studies assessing the effects of contraception on HIV susceptibility and mucosal immunity may generate disparate results in populations that differ by microbiota background or prevalence of undiagnosed genital tract infections. A high prevalence of asymptomatic infections among HC users that remain undiagnosed and untreated raises even more concerns in light of their combined effects on biomarkers of HIV risk. The molecular mechanisms of the vaginal microbiome's simultaneous interactions with hormones and HIV remain to be elucidated.

Add-back therapy with GnRH analogues for uterine fibroids.

BACKGROUND: Uterine fibroids (also known as leiomyomas) are the most common benign pelvic tumours among women. They may be asymptomatic, or may be associated with pelvic symptoms such as bleeding and pain. Medical treatment of this condition is limited and gonadotropin-releasing hormone (GnRH) analogues are the most effective agents. Long-term treatment with such agents, however, is restricted due to their adverse effects. The addition of other medications during treatment with GnRH analogues, a strategy known as add-back therapy, may limit these side effects. There is concern, however, that add-back therapy may also limit the efficacy of the GnRH analogues and that it may not be able to completely prevent their adverse effects. OBJECTIVES: To assess the short-term (within 12 months) effectiveness and safety of add-back therapy for women using GnRH analogues for uterine fibroids associated with excessive uterine bleeding, pelvic pain, or urinary symptoms. SEARCH METHODS: We searched electronic databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, PubMed, EMBASE, LILACS, CINAHL, PsycINFO; and electronic registries of ongoing trials including ClinicalTrials.gov, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform. All searches were from database inception to 16 June 2014. SELECTION CRITERIA: Randomized controlled trials (RCTs) that included women with uterine fibroids experiencing irregular or intense uterine bleeding, cyclic or non-cyclic pelvic pain, or urinary symptoms, and that compared treatment with a GnRH analogue plus add-back therapy versus a GnRH analogue alone or combined with placebo were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the identified titles and abstracts for potentially eligible records. Two review authors reviewed eligible studies and independently extracted data. Two authors independently assessed the studies' risk of bias. They assessed the quality of the evidence using GRADE criteria. MAIN RESULTS: Fourteen RCTs were included in the review. Data were extracted from 12 studies (622 women). The primary outcome was quality of life (QoL).Add-back therapy with medroxyprogesterone (MPA): no studies reported QoL or uterine bleeding. There was no evidence of effect in relation to bone mass (standardized mean difference (SMD) 0.38, 95% confidence interval (CI) -0.62 to 1.38, 1 study, 16 women, P = 0.45, low quality evidence) and MPA was associated with a larger uterine volume (mean difference (MD) 342.19 cm(3), 95% CI 77.58 to 606.80, 2 studies, 32 women, I(2) = 0%, low quality evidence).Tibolone: this was associated with a higher QoL but the estimate was imprecise and the effect could be clinically insignificant, small or large (SMD 0.47, 95% CI 0.09 to 0.85, 1 study, 110 women, P = 0.02, low quality evidence). It was also associated with a decreased loss of bone mass, which could be insignificant, small or moderate (SMD 0.36, 95% CI 0.03 to 0.7, 3 studies, 160 women, I(2) = 7%, moderate quality evidence). Tibolone may, however, have been associated with larger uterine volumes (MD 23.89 cm(3), 95% CI= 8.13 to 39.66, 6 studies, 365 women, I(2) = 0%, moderate quality evidence) and more uterine bleeding (results were not combined but three studies demonstrated greater bleeding with tibolone while two other studies demonstrated no bleeding in either group). Four studies (268 women; not pooled owing to extreme heterogeneity) reported a large benefit on vasomotor symptoms in the tibolone group.Raloxifene: there was no evidence of an effect on QoL (SMD 0.11, 95% CI -0.57 to 0.34, 1 study, 74 women, P = 0.62, low quality evidence), while there was a beneficial impact on bone mass (SMD 1.01, 95% CI 0.57 to 1.45, 1 study, 91 women, P < 0.00001, low quality evidence). There was no clear evidence of effect on uterine volume (MD 27.1 cm(3), 95% CI -17.94 to 72.14, 1 study, 91 women, P = 0.24, low quality evidence), uterine bleeding or severity of vasomotor symptoms (MD 0.2 hot flushes/day, 95% CI -0.34 to 0.74, 1 study, 91 women, P = 0.46, low quality evidence).Estriol: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. Add-back with estriol may have led to decreased loss of bone mass, from results of a single study (SMD 3.93, 95% CI 1.7 to 6.16, 1 study, 12 women, P = 0.0005, low quality evidence).Ipriflavone: no studies reported QoL, uterine size or uterine bleeding. Iproflavone was associated with decreased loss of bone mass in a single study (SMD 2.71, 95% CI 2.14 to 3.27, 1 study, 95 women, P < 0.00001, low quality evidence); there was no evidence of an effect on the rate of vasomotor symptoms (RR 0.67, 95% Cl 0.44 to 1.02, 1 study, 95 women, P = 0.06, low quality evidence).Conjugated estrogens: no studies reported QoL, uterine size, uterine bleeding or vasomotor symptoms. One study suggested that adding conjugated estrogens to GnRH analogues resulted in a larger decrease in uterine volume in the placebo group (MD 105.2 cm(3), 95% CI 27.65 to 182.75, 1 study, 27 women, P = 0.008, very low quality evidence).Nine of 12 studies were at high risk of bias in at least one domain, most commonly lack of blinding. All studies followed participants for a maximum of six months. This short-term follow-up is usually insufficient to observe any significant effect of the treatment on bone health (such as the occurrence of fractures), limiting the findings. AUTHORS' CONCLUSIONS: There was low or moderate quality evidence that tibolone, raloxifene, estriol and ipriflavone help to preserve bone density and that MPA and tibolone may reduce vasomotor symptoms. Larger uterine volume was an adverse effect associated with some add-back therapies (MPA, tibolone and conjugated estrogens). For other comparisons, outcomes of interest were not reported or study findings were inconclusive.

Contracepção injetável trimestral / Progestin-only injectable contraception

Os contraceptivos injetáveis trimestrais representam métodos de longo prazo muito utilizados, sendo acessíveis a grande contingente de pacientes. São altamente eficazes e com fácil posologia, colaborando com eficiente planejamento familiar. Suas taxas de gravidez oscilam entre 0,0 e 0,7/100 mulheres por ano. É método contraceptivo interessante para pacientes que não desejam ingestão de comprimidos, que apresentam contraindicações ao uso de estrogênios, que optam por amenorreia e para as adolescentes. No Brasil, é comercializado com a formulação de 150 mg de Acetato de Medroxiprogesterona de depósito (AMPD). Injeções intramusculares são capazes de inibir a ovulação e, também, alterarem o muco cervical e o endométrio. Seus efeitos adversos são reduzidos, destacando-se ganho de peso, dor abdominal, cefaleia, mudança de humor e diminuição do desejo sexual. Estudos atuais não demonstram maior risco de fraturas, apesar de haver discreta diminuição na densidade óssea. Apresenta benefícios relevantes como diminuição no risco de câncer endometrial, de câncer ovariano, de doença inflamatória pélvica e pode apresentar efeito benéfico nos sintomas da endometriose. Os autores realizaram revisão sobre o contraceptivo injetável trimestral priorizando seu modo de uso, efeitos benéficos, efeitos adversos e critérios de elegibilidade para sua prescrição.(AU)

The progestin-only injectable contraceptives are long-term methods widely used. They are accessible to large numbers of patients and are highly effective and easy to use. This collaborate with effective family planning. The pregnancy rates range between 0.0 and 0.7/100 women per years. They are a good alternative for contraception to patients who do not wish intake of pills, have contraindications to the use of estrogens, choose to amenorrhea and are adolescents. In Brazil it is marketed with the formulation of 150 mg of medroxyprogesterone acetate depot (DMPA). Intramuscular injections are able to inhibit ovulation and also modifies the cervical mucus and endometrium. Its adverse effects are few, especially weight gain, abdominal pain, headache, mood swings and decreased sexual desire. Current studies show no increased risk of fractures, although there is a slight decrease in bone density. It offers significant benefits such as reduced risk of endometrial cancer, ovarian cancer, pelvic inflammatory disease and may have beneficial effect on the symptoms of endometriosis. The authors conducted a review of the progestin-only injectable contraceptive focusing on its manner of use, benefits, side effects and eligibility criteria for prescription.(AU)

Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density.

This randomized double-blind study, with 24-week treatment and 24-week posttreatment periods, evaluated the effects of elagolix (150 mg every day, 75 mg twice a day) versus subcutaneous depot medroxyprogesterone acetate (DMPA-SC) on bone mineral density (BMD), in women with endometriosis-associated pain (n = 252). All treatments induced minimal mean changes from baseline in BMD at week 24 (elagolix 150 mg: -0.11%/-0.47%, elagolix 75 mg: -1.29%/-1.2%, and DMPA-SC: 0.99%/-1.29% in the spine and total hip, respectively), with similar or less changes at week 48 (posttreatment). Elagolix was associated with improvements in endometriosis-associated pain, assessed with composite pelvic signs and symptoms score (CPSSS) and visual analogue scale, including statistical noninferiority to DMPA-SC in dysmenorrhea and nonmenstrual pelvic pain components of the CPSSS. The most common adverse events (AEs) in elagolix groups were headache, nausea, and nasopharyngitis, whereas the most common AEs in the DMPA-SC group were headache, nausea, upper respiratory tract infection, and mood swings. This study showed that similar to DMPA-SC, elagolix treatment had minimal impact on BMD over a 24-week period and demonstrated similar efficacy on endometriosis-associated pain.

A four week randomised control trial of adjunctive medroxyprogesterone and tamoxifen in women with mania.

Emerging research has suggested that hormone treatments such as selective oestrogen receptor modulators (SERMs) or progestins may be useful in the treatment of mania. The current pilot study compared the use of the SERM tamoxifen and the progestin medroxyprogesterone acetate (MPA), as an adjunct to mood stabiliser medications, for the treatment of mania symptoms in 51 women in a 28-day double blind, placebo controlled study. The primary outcome was the change between baseline and day 28 mania scores as measured by the Clinician Administered Rating Scale for Mania (CARS-M). Adjunctive MPA treatment provided greater and more rapid improvement in mania symptoms compared with adjunctive placebo and tamoxifen treatment. Adjunctive therapy with MPA may be a potentially useful new treatment for persistent mania, leading to a greater and more rapid resolution of symptoms compared with mood stabiliser treatment alone.

Oestrogens promote tumorigenesis in a mouse model for colitis-associated cancer.

BACKGROUND: Hormone replacement therapy increases the risk of developing ulcerative colitis in postmenopausal women. Chronic intestinal inflammation predisposes to colon cancer development, but effects of female hormones on colitis-associated cancer development have not been examined. AIM: To investigate the role of female hormones in the dextran sodium sulfate (DSS)-azoxymethane (AOM) mouse model for colitis-associated cancer. DESIGN: We performed ovariectomies, or sham operations, on mice, and supplemented these animals with indicated hormones. Additionally, we used oestrogen receptor α or ß (Erα or Erß) mutant mice. To study colitis or colitis-associated cancer, we used DSS only, or DSS and AOM, respectively. RESULTS: Ovariectomy protects female mice against colitis-associated tumour development. Hormone replacement in ovariectomised mice with either oestradiol (E2), medroxyprogesterone acetate or a combination of both suggests that oestrogens are the ovary-derived factor that promotes tumour development in the context of inflammatory damage. E2-treated animals showed increased clinical symptoms and Il-6 production upon DSS-induced colitis and enhanced epithelial proliferation. Treatment with E2 markedly increased the numbers of polyps in ovariectomised mice and also strongly promoted tumour progression with all E2-treated animals developing at least one invasive adenocarcinoma, whereas, placebo-treated animals developed adenomas only. Using Er mutant mice, we find that the protumorigenic effect of oestrogen depends on both Erα and Erß. CONCLUSIONS: Our results suggest that oestrogens promote inflammation-associated cancer development by impairing the mucosal response to inflammatory damage.

Altered arterial stiffness in male-to-female transsexuals undergoing hormonal treatment.

AIM: Male-to-female (MTF) transsexuals are treated with estrogen with and without progestin through a variety of routes. The aim of this study is to evaluate the arterial stiffness in MTF transsexuals undergoing hormonal treatment. METHODS: We evaluated the arterial stiffness in 156 MTF transsexuals (22 untreated and 129 treated with estrogen only or plus progestin) using a volume-plethysmographic apparatus equipped with a multi-element applanation tonometry sensor. RESULTS: MTF transsexuals treated with parenteral estrogen were significantly older than untreated MTF transsexuals. Hematocrit, uric acid and activated partial thromboplastin time in treated MTF transsexuals were significantly lower than in untreated MTF transsexuals. The level of high-density lipoprotein cholesterol in MTF transsexuals treated with oral estrogen was significantly higher than in untreated MTF transsexuals or those treated with parenteral estrogen with and without progestin. The systolic blood pressure in MTF transsexuals treated with estrogen only is significantly lower than that in untreated MTF transsexuals. The brachial-ankle pulse wave velocity was significantly decreased in MTF transsexuals treated with estrogen compared to that in untreated MTF transsexuals or in those treated with estrogen plus progestin. The carotid augmentation index in MTF transsexuals treated with oral estrogen was significantly lower than that in MTF transsexuals treated with parenteral estrogen or oral estrogen plus progestin. CONCLUSIONS: Estrogen treatment is likely to have some beneficial effects on lipid metabolism and vascular function in MTF transsexuals; however, progestin administered with estrogen may have adverse effects on arterial stiffness.

Breast tenderness and breast cancer risk in the estrogen plus progestin and estrogen-alone women's health initiative clinical trials.

The associations between breast tenderness during use of conjugated equine estrogen (CEE) therapy with or without medroxyprogesterone (MPA) therapy and subsequent breast cancer risk are unknown. We analyzed data from the Women's Health Initiative Estrogen plus Progestin (N = 16,608, 5.6 years intervention) and estrogen-alone (N = 10,739, 6.8 years intervention) clinical trials until trial close-out (Spring 2005). At baseline and annually, participants underwent mammography and clinical breast exam. Self-reported breast tenderness was assessed at baseline and 12 months. Invasive breast cancer was confirmed by medical record review. The risk of new-onset breast tenderness after 12 months was significantly higher among women assigned to active therapy than placebo (CEE-alone vs. placebo risk ratio [RR] 2.15, 95% confidence interval [CI] 1.97-2.35; CEE + MPA vs. placebo RR 3.07, 95% CI 2.85-3.30). CEE + MPA doubled the risk of invasive breast cancer among women with baseline breast tenderness (hazard ratio [HR] 2.16, 95% CI 1.29-3.74), but had a smaller effect among women without baseline breast tenderness (HR 1.17; 95% CI 0.97-1.41). New-onset breast tenderness was associated with a higher risk of breast cancer among women assigned to CEE + MPA (HR 1.33, 95% CI 1.02-1.72, P = 0.03), but not among women assigned to CEE-alone (HR 0.98, 95% CI 0.62-1.53). New-onset breast tenderness during use of CEE + MPA was associated with increased subsequent breast cancer risk. The association of CEE + MPA therapy with increased breast cancer risk was especially pronounced among women with baseline breast tenderness.

Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia.

PURPOSE: A phase III, randomized study was carried out to establish the most effective and safest treatment to improve the primary endpoints of cancer cachexia-lean body mass (LBM), resting energy expenditure (REE), and fatigue-and relevant secondary endpoints: appetite, quality of life, grip strength, Glasgow Prognostic Score (GPS) and proinflammatory cytokines. PATIENTS AND METHODS: Three hundred thirty-two assessable patients with cancer-related anorexia/cachexia syndrome were randomly assigned to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, L-carnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. RESULTS: Analysis of variance showed a significant difference between treatment arms. A post hoc analysis showed the superiority of arm 5 over the others for all primary endpoints. An analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) significantly increased in arm 5. REE decreased significantly and fatigue improved significantly in arm 5. Appetite increased significantly in arm 5; interleukin (IL)-6 decreased significantly in arm 5 and arm 4; GPS and Eastern Cooperative Oncology Group performance status (ECOG PS) score decreased significantly in arm 5, arm 4, and arm 3. Toxicity was quite negligible, and was comparable between arms. CONCLUSION: The most effective treatment in terms of all three primary efficacy endpoints and the secondary endpoints appetite, IL-6, GPS, and ECOG PS score was the combination regimen that included all selected agents.

Menopausal hormone therapy, hormone receptor status, and lung cancer in women.

Gender differences in lung cancer incidence and outcome suggest a potential role for reproductive hormones. However, observational studies regarding menopausal hormone therapy use and lung cancer have given mixed results. Some have associated hormone therapy use with increased lung cancer risk, while others have shown no effect or found lower lung cancer risk in hormone therapy users. Against this background the Women's Health Initiative (WHI) randomized controlled trial evaluating conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in postmenopausal women identified an increase in malignancies in the hormone therapy group during the post intervention period. Post hoc analyses identified a statistically significant increase in deaths from lung cancer for women in the hormone group largely related to effects on non-small cell lung cancer (NSCLC). The NSCLCs were more commonly poorly differentiated and were diagnosed at a metastatic stage, suggesting a hormone effect on already established lung cancer growth. Ongoing preclinical and clinical analyses have identified estrogen receptors in the nucleus and cytoplasm of lung tissue and lung cancers. More recently, intriguing associations among estrogen receptor expression, lung cancer histology, clinical prognosis, and epidermal growth factor receptor (EGFR) mutations have been reported. The WHI clinical findings should be integrated into risk-benefit discussion with women considering combined hormone therapy use. In addition, the findings, together with ongoing studies evaluating estrogen receptor status and function, support further efforts to develop lung cancer intervention strategies targeting estrogen receptor expression.

Discontinuing postmenopausal hormone therapy: an observational study of tapering versus quitting cold turkey: is there a difference in recurrence of menopausal symptoms?

OBJECTIVE: Because no current evidence-based guidelines for postmenopausal hormone therapy (HT) discontinuation strategies exist, we compared female veterans who tapered HT to those who stopped abruptly with regard to patient-specific health factors and recurrence of menopausal symptoms. METHODS: We identified female veterans who used combined estrogen/medroxyprogesterone HT in 2001 using the VA Pharmacy Benefits Management database. We then randomly sorted and selected 4,000 women for a mailed invitation to participate in a HT survey. Women who agreed to participate were mailed the National Women Veterans Hormone Replacement Survey. RESULTS: Of 836 participants who discontinued HT, 75% stopped cold turkey and 25% tapered. In bivariate analysis, taperers were more likely to report higher incomes, less smoking, and more use of alternatives such as vitamin E, other dietary supplements, and exercise or yoga for menopausal symptoms. They also more frequently reported discussions of menopausal symptoms with providers and used HT for menopausal symptoms and had longer median years of HT (P

Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women's health initiative trials of hormone therapy.

BACKGROUND: Clinical trials of postmenopausal hormone therapy (HT) have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy and no overall benefit. METHODS: This nested case-control study evaluates a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD in the 4 years after randomization and assesses whether any of these markers modified or mediated the initially increased risk associated with HT in postmenopausal women aged 50 to 79 years at baseline. Conjugated equine estrogens, 0.625 mg/d, or placebo was given to 10 739 hysterectomized women, and the same estrogen plus medroxyprogesterone acetate, 2.5 mg/d, was given to 16 608 women with an intact uterus. RESULTS: In multivariate-adjusted analyses of 359 cases and 820 controls in the combined trials, baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin 6, matrix metalloproteinase 9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with HT so that women with higher levels were at higher risk for CHD when given HT (P = .03 for interaction). The levels of several biomarkers were changed by HT, but these changes did not seem to be associated with future CHD events. CONCLUSIONS: Several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, but only low-density lipoprotein cholesterol modified the effect of HT. Further research is needed to identify the mechanisms by which HT increases the risk of CHD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

Chronic pelvic pain in women.

The etiology of chronic pelvic pain in women is poorly understood. Although a specific diagnosis is not found in the majority of cases, some common diagnoses include endometriosis, adhesions, irritable bowel syndrome, and interstitial cystitis. The initial history and physical examination can narrow the diagnostic possibilities, guide any subsequent evaluation, and rule out malignancy or significant systemic disease. If the initial evaluation does not reveal a specific diagnosis, a limited laboratory and ultrasound evaluation can clarify the diagnosis, as well as rule out serious disease and reassure the patient. Few treatment modalities have demonstrated benefit for the symptoms of chronic pelvic pain. The evidence supports the use of oral medroxyprogesterone, goserelin, adhesiolysis for severe adhesions, and a multidisciplinary treatment approach for patients without a specific diagnosis. Less supporting evidence is available for oral analgesics, combined oral contraceptive pills, gonadotropin-releasing hormone agonists, intramuscular medroxyprogesterone, trigger point and botulinum A toxin injections, neuromodulative therapies, and hysterectomy.

Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling.

Tibolone, a tissue-selective compound with a combination of estrogenic, progestagenic, and androgenic properties, is used as an alternative for estrogen or estrogen plus progesterone hormone therapy for the treatment of symptoms associated with menopause and osteoporosis. The current study compares the endometrial gene expression profiles after short-term (21 days) treatment with tibolone to the profiles after treatment with estradiol-only (E(2)) and E(2) + medroxyprogesterone acetate (E(2) + MPA) in healthy postmenopausal women undergoing hysterectomy for endometrial prolapse. The impact of E(2) treatment on endometrial gene expression (799 genes) was much higher than the effect of tibolone (173 genes) or E(2) + MPA treatment (174 genes). Furthermore, endometrial gene expression profiles after tibolone treatment show a weak similarity to the profiles after E(2) treatment (overlap 72 genes) and even less profile similarity to E(2) + MPA treatment (overlap 17 genes). Interestingly, 95 tibolone-specific genes were identified. Translation of profile similarity into biological processes and pathways showed that ER-mediated downstream processes, such as cell cycle and cell proliferation, are not affected by E2 + MPA, slightly by tibolone, but are significantly affected by E(2). In conclusion, tibolone treatment results in a tibolone-specific gene expression profile in the human endometrium, which shares only limited resemblance to E(2) and even less resemblance to E2 + MPA induced profiles.

Clinical applications of hormonal therapy in ovarian cancer.

The ovary is an endocrine organ and an end organ. Hormones and their receptors have been associated with ovarian cancer and may be related to its causation. Some data suggest that hormonal therapies may have some effect on ovarian cancer in palliative settings. No hormonal therapy is approved by the US Food and Drug Administration (FDA) for the treatment of any type of ovarian malignancy nor is it listed as an active agent by any of the authoritative compendia. Because of the endocrine associations with ovarian cancer, the minimal side effects, and demonstrated activity of hormonal therapies in other endocrine-associated malignancies, further study is needed.