Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendations

Heidi D. Nelson, MD, MPH; Miranda Walker, MA; Bernadette Zakher, MBBS; and Jennifer Mitchell, BA

+ Author Affiliations

From Oregon Evidence-based Practice Center, Oregon Health & Science University, and Providence Cancer Center, Providence Health & Services, Portland, Oregon.

Ann Intern  Med  2012 , publ. online 29 May

Abstract

Background: Menopausal hormone therapy to prevent chronic conditions is currently not recommended because of its adverse effects.

Purpose: To update evidence about the effectiveness of hormone therapy in reducing risk for chronic conditions and adverse effects, and to examine whether outcomes vary among women in different subgroups.

Data Sources: MEDLINE (January 2002 to November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the 3rd quarter of 2011), Scopus, and reference lists.

Study Selection: Randomized, placebo-controlled trials of menopausal hormone therapy published in English since 2002 that assessed primary prevention of chronic conditions.

Data Extraction: Investigators extracted data on participants, study design, analysis, follow-up, and results; 2 investigators independently rated study quality by using established criteria.

Data Synthesis: 9 fair-quality trials met the inclusion criteria. The Women's Health Initiative reported most of the results, had 11 years of follow-up, and had data most applicable to postmenopausal women in the United States. It showed that estrogen plus progestin reduced fractures (46 fewer per 10 000 woman-years) and increased invasive breast cancer (8 more per 10 000 woman-years), stroke (9 more per 10 000 woman-years), deep venous thrombosis (12 more per 10 000 woman-years), pulmonary embolism (9 more per 10 000 woman-years), lung cancer death (5 more per 10 000 woman-years), gallbladder disease (20 more per 10 000 woman-years), dementia (22 more per 10 000 woman-years), and urinary incontinence (872 more per 10 000 woman-years). Estrogen-only therapy reduced fractures (56 fewer per 10 000 woman-years) and invasive breast cancer incidence (8 fewer per 10 000 woman-years) and death (2 fewer per 10 000 woman-years) and increased stroke (11 more per 10 000 woman-years), deep venous thrombosis (7 more per 10 000 woman-years), gallbladder disease (33 more per 10 000 woman-years), and urinary incontinence (1271 more per 10 000 woman-years). Outcomes did not consistently differ by age or comorbid conditions.

Limitation: Limitations of the trials included low adherence, high attrition, inadequate power to detect risks for some outcomes, and evaluation of few regimens.

Conclusion: Estrogen plus progestin and estrogen alone decreased risk for fractures but increased risk for stroke, thromboembolic events, gallbladder disease, and urinary incontinence. Estrogen plus progestin increased risk for breast cancer and probable dementia, whereas estrogen alone decreased risk for breast cancer.

Primary Funding Source: Agency for Healthcare Research and Quality.

Editorial comment: For sure it was not the intention of the authors of this excellent systematic review but at the end of the day the colleague who has to decide together with his menopause patient whether hormonal replacement therapy should be initiated or not may even be more confused now regarding potential benefits of either estrogen or combined estrogen plus progestin replacement therapy. No question the benefits and the potential risks of either replacement therapy have to be weighed up against the patients’ complaints on an individual basis.

FDA approves Stendra for erectile dysfunction

For Immediate Release: April 27, 2012
Media Inquiries: Stephanie Yao, 301-796-0394, stephanie.yao@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA

The U.S. Food and Drug Administration today approved Stendra (avanafil), a new drug to treat erectile dysfunction.

Erectile dysfunction is when a man has trouble getting or keeping an erection. An estimated 30 million men in the United States are affected by erectile dysfunction.
Stendra is a pill that patients take on an as-needed basis 30 minutes before sexual activity. Doctors should prescribe the lowest dose of Stendra that provides benefit.
“This approval expands the available treatment options to men experiencing erectile dysfunction, and enables patients, in consultation with their doctor, to choose the most appropriate treatment for their needs,” said Victoria Kusiak, M.D., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research.

Stendra belongs to a class of drugs called phosphodiesterase type 5 (PDE5) inhibitors, which are used to help increase blood flow to the penis. As with other PDE5 inhibitors, Stendra should not be used by men who also take nitrates, commonly used to treat chest pain (angina), because the combination can cause a sudden drop in blood pressure.
PDE5 inhibitors may rarely cause color vision changes. In rare instances, men taking PDE5 inhibitors have reported a sudden loss of vision in one or both eyes. Sudden loss or decrease in hearing has also been reported in patients taking PDE5 inhibitors. Patients who experience a sudden loss of vision or hearing should stop taking PDE5 inhibitors, including Stendra, and call a doctor right away.

The most common side effects reported in greater than 2 percent of patients in the clinical studies of Stendra include headache, redness of the face and other areas (flushing), nasal congestion, common cold-like symptoms (nasopharyngitis), and back pain. In rare cases, patients taking Stendra and other PDE5 inhibitors may get an erection lasting four hours or longer that will not go away (priapism). If this happens, patients should seek immediate medical care.
Stendra’s safety and efficacy were established in three double-blind, placebo-controlled clinical studies. A total of 1,267 patients were randomly assigned to take Stendra for up to 12 weeks at doses of 50 milligrams (mg), 100 mg or 200 mg, or a placebo as needed about 30 minutes before sexual activity.

At the start of the studies and every four weeks thereafter, patients completed questionnaires to evaluate erectile function, vaginal penetration and successful intercourse. Results showed patients taking Stendra experienced statistically significant improvement in all three endpoints for all three doses of Stendra studied.
To further evaluate Stendra’s safety, a subset of patients from two of the studies were enrolled in another trial to receive up to an additional 40 weeks of treatment. Patients were initially given Stendra at the 100 mg dose, but could have their dose increased to 200 mg or decreased to 50 mg based on their individual response to treatment. Results showed that the side effects commonly reported in patients using Stendra did not worsen over time.
Stendra is marketed by Mountain View, Calif.-based VIVUS Inc.

Editorial comment: Welcome the new PDE 5 inhibitor Avanafil. Many may ask whether we need more PDE 5 inhibitors but compared to  the field of cardiovascular diseases the Sexual Medicine discipline has only few effective drugs. What does this new PDE 5 inhibitor add to the ED management what other do not have ? Regarding the efficacy and safety data the outcome of Avanafil trials are in line with the other PDE 5 inhibitors in this field. In terms of the pharmacokinetics and the findings of the clinical trials Avanafil seems to provide a very rapid onset of action and may therefore especially comply with the spontaneity aspects of ED drug management as is hoped for and expected by our couples.

Subclinical Hyperthyroidism and the Risk of Coronary Heart Disease and Mortality

Tinh-Hai Collet, MD; Jacobijn Gussekloo, MD, PhD; Douglas C. Bauer, MD; Wendy P. J. den Elzen, PhD; Anne R. Cappola, MD, ScM; Philippe Balmer, BSc; Giorgio Iervasi, MD; Bjørn O. Åsvold, MD, PhD; José A. Sgarbi, MD; Henry Völzke, MD; Bariş Gencer, MD; Rui M. B. Maciel, MD; Sabrina Molinaro, PhD; Alexandra Bremner, PhD; Robert N. Luben, PhD; Patrick Maisonneuve, Ing; Jacques Cornuz, MD, MPH; Anne B. Newman, MD, MPH; Kay-Tee Khaw, MD; Rudi G. J. Westendorp, MD, PhD; Jayne A. Franklyn, MD, PhD, FRCP, FMedSci; Eric Vittinghoff, PhD; John P. Walsh, MBBS, FRACP, PhD; Nicolas Rodondi, MD, MAS; for the Thyroid Studies Collaboration

Arch Intern Med. 2012;(): 1-11

Background Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting. We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.
Methods Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.
Results Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio [HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR, 1.29, 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95% CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43). Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% for AF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 compared with thyrotropin level between 0.10 and 0.44 mIU/L (for both, P value for trend, ≤.03).
Conclusions Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.
Editorial comment: The data of this prospective cohort series comprising more than 52.000 patients are of major clinical importance considering the fact that more than 4 % had subclinical hypothyroidism and 14,5 % of them showing an attributable risk of 14,5 % for total mortality and in 41,5 % for atrial fibrillation. The data of these representative series underline the importance of routine determination of TSH and the need that especially those patients with TSH < 0,1 mIU/L undergo an  appropriate clinical management in order to avoid detrimental long-term sequelae.

Association of hypogonadism with vitamin D status: the European Male Ageing Study.

Lee DM, Tajar A, Pye SR, Boonen S, Vanderschueren D, Bouillon R, O'Neill TW, Bartfai G, Casanueva FF, Finn JD, Forti G, Giwercman A, Han TS, Huhtaniemi IT, Kula K, Lean ME, Pendleton N, Punab M, Wu FC; EMAS study group.

Collaborators (29)
Forti G, Petrone L, Corona G, Vanderschueren D, Boonen S, Borghs H, Kula K, Slowikowska-Hilczer J, Walczak-Jedrzejowska R, Huhtaniemi I, Giwercman A, Wu F, Silman A, Pendleton N, O'Neill T, Finn J, Steer P, Tajar A, Lee D, Pye S, Casanueva F, Lage M, Castro AI, Bartfai G, Földesi I, Fejes I, Punab M, Korrovitz P, Jiang M.

Eur J Endocrinol. 2012 Jan;166(1):77-85

Abstract

OBJECTIVE:

Interrelationships between hormones of the hypothalamic-pituitary-testicular (HPT) axis, hypogonadism, vitamin D and seasonality remain poorly defined. We investigated whether HPT axis hormones and hypogonadism are associated with serum levels of 25-hydroxyvitamin D (25(OH)D) in men.

DESIGN AND METHODS:
Cross-sectional survey of 3369 community-dwelling men aged 40-79 years in eight European centres. Testosterone (T), oestradiol (E(2)) and dihydrotestosterone were measured by gas chromatography-mass spectrometry; LH, FSH, sex hormone binding globulin (SHBG), 25(OH)D and parathyroid hormone by immunoassay. Free T was calculated from total T, SHBG and albumin. Gonadal status was categorised as eugonadal (normal T/LH), secondary (low T, low/normal LH), primary (low T, elevated LH) and compensated (normal T, elevated LH) hypogonadism. Associations of HPT axis hormones with 25(OH)D were examined using linear regression and hypogonadism with vitamin D using multinomial logistic regression.

RESULTS:
In univariate analyses, free T levels were lower (P=0.02) and E(2) and LH levels were higher (P<0.05) in men with vitamin D deficiency (25(OH)D <50 nmol/l). 25(OH)D was positively associated with total and free T and negatively with E(2) and LH in age- and centre-adjusted linear regressions. After adjusting for health and lifestyle factors, no significant associations were observed between 25(OH)D and individual hormones of the HPT axis. However, vitamin D deficiency was significantly associated with compensated (relative risk ratio (RRR)=1.52, P=0.03) and secondary hypogonadism (RRR=1.16, P=0.05). Seasonal variation was only observed for 25(OH)D (P<0.001).

CONCLUSIONS:
Secondary and compensated hypogonadism were associated with vitamin D deficiency and the clinical significance of this relationship warrants further investigation.

Editorial comment: The epidemiological data of this representative series provide evidence that hypogonadism is significantly associated with vitamin D 3 deficiency. The clinical consequence for all of us may be that in the future vitamin D 3 should become  a routine lab parameter in all our hypogonadal men with many of them finally needing both T- and vitamin D3 substitution therapy.

Article of the month April

Testosterone Treatment and Mortality in Men with Low Testosterone Levels

Molly M. Shores, Nicholas L. Smith, Christopher W. Forsberg, Bradley D. Anawalt and Alvin M. Matsumoto

The Journal of Clinical Endocrinology & Metabolism 2012, published online before print April 11, 2012

Abstract

Context:

Low testosterone levels in men have been associated with increased mortality. However, the influence of testosterone treatment on mortality in men with low testosterone levels is not known.

Objective:

The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels.

Design:

This was an observational study of mortality in testosterone-treated compared with untreated men, assessed with time-varying, adjusted Cox proportional hazards regression models. Effect modification by age, diabetes, and coronary heart disease was tested a priori.

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Article of the month March

Empirical Medical Therapy for Idiopathic Male Infertility: A Survey of the American Urological Association

Edmund Y. Ko, Kashif Siddiqi, Robert E. Brannigan, Edmund S. Sabanegh Jr

The Journal of Urology 2012 , 187, 973-978

Purpose:

We determined empirical medical therapy practice patterns for idiopathic infertility.

Materials and Methods:

We performed a survey of 7,745 practicing American Urological Association members from July to November 2010. Respondents were questioned on empirical medical therapy use, patient evaluation and selection, and preferred medications.

Results:

A total of 387 urologists (5%) participated in the survey, of whom 16% had infertility fellowship training, two-thirds used empirical medical therapy and 78% treated with empirical medical therapy and surgery. Laboratory values important for identifying ideal candidates include sperm concentration, serum follicle-stimulating hormone and serum testosterone. The most common medications used were clomiphene citrate, human chorionic gonadotropin and anastrozole. Of respondents 25% would treat infertile males with testosterone while the patient actively pursued pregnancy. Overall 60.5% of respondents would treat with empirical therapy for 3 to 6 months. Of fellowship trained and general urologist respondents 70% and 47%, respectively, counseled patients that empirical medical therapy has unknown effects on pregnancy and sperm count.

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Article of the month February

POLICY STATEMENT

HPV Vaccine Recommendations

Pediatrics 2012;129:602–605

Abstract:

On October 25, 2011, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention recommended that the quadrivalent human papillomavirus vaccine (Gardasil; Merck & Co, Inc, Whitehouse Station, NJ) be used routinely in males. The American Academy of Pediatrics has reviewed updated data provided by the Advisory Committee on Immunization Practices on vaccine efficacy, safety, and cost-effectiveness as well as programmatic considerations and supports this recommendation. This revised statement updates recommendations for human papillomavirus immunization of both males and females.

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Article of the month January

Standard-dose and high-dose daily antiviral therapy for short episodes of genital HSV-2 reactivation: three randomised, open-label, cross-over trials

Dr Christine Johnston MD a e   , Misty Saracino PhD b, Steve Kuntz PA-C b, Amalia Magaret PhD b e, Stacy Selke MS b, Meei-li Huang PhD b e, Joshua T Schiffer MD a e, Prof David M Koelle MD a b c e, Prof Lawrence Corey MD a b e, Prof Anna Wald MD a b d e

The Lancet,2012  Early Online Publication, 5 January 2012

Summary

Background:

Skin and mucosal herpes simplex virus type 2 (HSV-2) shedding predominantly occurs in short subclinical episodes. We assessed whether standard-dose or high-dose antiviral therapy reduces the frequency of such shedding.

Methods:

HSV-2-seropositive, HIV-seronegative people were enrolled at the University of Washington Virology Research Clinic (WA, USA). We did three separate but complementary open-label cross-over studies comparing no medication with aciclovir 400 mg twice daily (standard-dose aciclovir), valaciclovir 500 mg daily (standard-dose valaciclovir) with aciclovir 800 mg three times daily (high-dose aciclovir), and standard-dose valaciclovir with valaciclovir 1 g three times daily (high-dose valaciclovir).

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