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HRT : Oral versus Transdermal 

Selecting Menopausal Estrogen Therapy: Oral or Transdermal? Case Study

The following test-and-teach case is an educational program modeled on the interactive grand rounds approach. The questions are designed to test your current knowledge. After each question, you will be able to see whether you answered the question correctly. The author will then present referenced information to support the most appropriate answer choice. Please note that these questions are designed to challenge you, and you are not penalized for answering the questions incorrectly.

 

Patient History and Introduction

 

Andrea Sanchez is a 52-year-old Mexican-American woman who presents for her annual checkup at your internal medicine office in San Antonio. Ms. Sanchez reports that for the last 7 weeks she has been suffering from severe hot flashes that occur 2 to 3 times a day almost every day and disrupted sleep from hot flashes a few nights a week. For the last 5 weeks, she has tried an herbal supplement advertised for hot flashes, but has had no relief.

Ms. Sanchez has given birth to two children and reports that, at age 43, she had a hysterectomy (with ovarian conservation) due to fibroids. She smokes almost half a pack of cigarettes a day. She has no history of breast cancer or cardiovascular disease (CVD). She does not have a family history of breast cancer, but both her mother and father suffered from CVD, the cause of their premature deaths. Ms. Sanchez has never used any type of prescription medication, including any estrogen-containing hormone therapy (HT).

Her physical examination reveals that she weighs 165 lb and is 5'2" tall. Her body mass index (BMI) is 31.2 kg/m2 and her waist circumference is 34 inches (86.5 cm). Her blood pressure is 136/77 mm Hg. Her gynecological exam confirms the hysterectomy and intact ovaries. Vaginal examination is unremarkable.

Laboratory tests reveal that her fasting plasma glucose is 115 mg/dL and her thyroid function test is normal. Her lipid profile is as follows:

• Total cholesterol = 227 mg/dL

• Low-density lipoprotein cholesterol (LDL-C) = 130 mg/dL

• High-density lipoprotein cholesterol (HDL-C) = 40 mg/dL

• Non-HDL-C = 187 mg/dL

• Triglycerides = 285 mg/dL

You diagnose that Ms. Sanchez suffers from metabolic syndrome and high cholesterol. Explaining her increased risk for CVD and diabetes, you also provide counseling regarding a number of lifestyle changes, including dieting, exercising, and stopping smoking. You prescribe 10 mg per day of rosuvastatin to lower her LDL-C level and metformin 500 mg po bid to help reduce her risk of diabetes.

You explain to Ms. Sanchez that she is in the early postmenopause stage and that her hot flashes are probably the result of menopause. Although you would prefer that the various health risks revealed during her examinations -- hypertension, high glucose, and high cholesterol -- be better controlled before recommending systemic ET, you proceed with that recommendation because her severe hot flashes are significantly affecting her quality of life. You know that lifestyle modification and nonprescription remedies are not proven to relieve severe hot flashes.

You advise Ms. Sanchez that choosing menopausal HT is an individual decision. Then you continue with a description of the risks and benefits of low-dose systemic ET and the different routes of administration, doses, and the possible adverse effects. You also explain that because she no longer has an intact uterus, no concomitant progestogen therapy is required to protect the uterus from the stimulatory effects of ET.

 

 

The decline in estradiol production that results around the time of menopause can occur over a period of several years or quite abruptly subsequent to surgical removal of the ovaries, chemotherapy, radiation, or acquired disorders. As estradiol production wanes, many women experience vasomotor symptoms (VMS), breast tenderness, insomnia, vulvovaginal dryness, and/or mood changes. VMS are common, usually expressed as hot flashes and/or night sweats. They can be very disruptive and diminish quality of life. Using a nationally representative sample of 4402 US women ages 40 to 65,[1] VMS were reported in 79% of perimenopausal women and 65% of postmenopausal women. Those with night sweats had an average of 2.4 moderate, 3.2 severe, and 2.7 very severe night sweats in a typical night. Overall, 9% of perimenopausal women and 7% of postmenopausal women reported seven or more moderate to very severe VMS in a typical day.

While long-term endogenous estrogen depletion can increase the risk of CVD and osteoporosis, it also results in vaginal and vulvar atrophy. Women who experience more frequent and severe symptoms are more likely to have uncontrolled risk factors for vascular disease and/or other comorbidities.[2,3]

Ms. Sanchez has severe VMS at age 52. She has read some reports about the Women's Health Initiative (WHI) and is worried about the risks of ET. At this time, counseling her on the absolute risks studied in the literature is warranted, explaining at the same time that ET -- or estrogen-progestogen therapy (EPT) for women with an intact uterus -- is the current standard of care for treatment of moderate to severe VMS.[2]

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|The Women's Health Initiative (WHI) was a landmark study that influenced the prescribing patterns of ET/EPT and product labeling by the US |

|Food and Drug Administration (FDA). Which of the following statements is not true? |

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|The FDA labels all forms of estrogen with a warning that it should not be used to protect against CVD. |

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|This warning applies regardless of route of delivery of the ET/EPT. |

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|Transdermal estrogen, because of reduced risk, is not under this advisory. |

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In the wake of WHI and the Heart and Estrogen/progestin Replacement Study (HERS), the FDA began requiring a black box warning on all postmenopausal estrogen products regarding potential risks. Based on the results from these large trials, in which oral ET was given in a continuous regimen for postmenopausal women (average age, 62.5 y), they warned that ET or EPT should not be used solely for the prevention of CVD. The FDA recommended the use of the lowest dose of estrogen for the shortest duration to relieve symptoms.

 

Unfortunately, the WHI evaluated only one type of estrogen (conjugated estrogens [CE]), alone or with one progestogen (the progestin medroxyprogesterone acetate [MPA]), and only one route of administration (oral). Women who had a hysterectomy were treated with 0.625 mg oral CE daily, adding 2.5 mg oral MPA for those women with a uterus. The average age of participants was 63 years. In this clinical trial, ET and EPT users in total had a higher risk of venous thromboembolism (VTE), stroke, and coronary heart disease early in the trial compared with placebo. However, when the data were broken out for younger women who initiated HT closer to menopause, these increased risks were not observed.[4,5] In addition, results may or may not be different with different doses of the same products, with other estrogen or progestogen products, or for transdermal or vaginal routes of ET administration. Any clinical trial is careful to delineate inclusion and exclusion criteria. While this helps with understanding efficacy, it tends to limit generalizability. When comorbidities are present, increasingly common with age, it seems prudent to choose an ET regimen based on optimum efficacy and fewest side effects.

 

Prescription systemic (ie, oral or transdermal, not vaginal) ET or EPT drugs are the only treatments currently government approved in the United States and Canada for VMS relief -- and are the only therapies proven to relieve severe VMS. A wide variety of estrogen and progestogen types, routes of administration, doses, and regimens are available. The NAMS Web site offers a complete list of HT products available in the United States and Canada for postmenopausal use.

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|When estrogen is given orally, which of the following is true? |

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|Circulating estradiol is greater than circulating estrone. |

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|Circulating estrone is greater than estradiol with oral ET. |

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|These levels are the same and they both go up. |

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Bottom of Form

Ms. Sanchez has agreed with your recommendation regarding starting systemic ET. You now discuss the potential benefits and risks of transdermal therapy compared with oral therapy.

Oral ET administration is associated with gastrointestinal and first-pass liver metabolism and stimulation.[6] Extensive metabolism of oral estrogens results in conversion of a large portion of the dose to estrone and its conjugates, which have less estrogenic activity than estradiol. There is a higher estrone-to-estradiol ratio in the bloodstream. This ratio is opposite to the physiologic ratio in premenopausal women. During the first-pass effect, some metabolites of CE appear to have antiestrogenic or unrecognized pharmacologic activity -- with either having the potential to be an advantage or a disadvantage.[7]

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|The potential safety of transdermal versus oral estrogen is related to which of the following? |

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|The lack of an effect on the enterohepatic circulation |

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|Lower dose |

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|The lack of an effect on the enterohepatic circulation and lower dose |

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When estrogen is delivered transdermally, it can be prescribed in lower doses than oral administration because it is not dependent on gastrointestinal absorption or subjected to first-pass hepatic metabolism. Transdermal estradiol is delivered directly to the circulation and bypasses the first-pass and gastrointestinal metabolism to estrone and conjugates. When transdermal ET is used, the estradiol-estrone ratio is normalized. The clinical relevance of this is not clear.

Both transdermal ET and EPT have been shown in randomized clinical trials (RCTs) to provide clinically significant VMS relief compared with placebo.[8,9]

 

In an open-label, 1-year RCT, 774 postmenopausal women received 50 mcg of continuous transdermal estradiol with either sequential or continuous transdermal progestin. The average number of VMS per day decreased up to 90% from prestudy. This reduction was unaffected by the type of progestin used (norethisterone acetate [NETA] or dydrogesterone).[10]

A recent multicenter RCT evaluating 454 women with at least eight moderate VMS per day achieved VMS reduction with three doses of a transdermal estradiol spray.[11] VMS reduction with the spray appears to be comparable to results with higher doses of estradiol given by a patch in conjunction with progestins. Oral estrogen and progestin preparations used in increasingly lower doses had similar reported efficacy.[12-15]

 

Few head-to-head comparisons have been performed comparing efficacy for VMS relief by route of delivery.[16]Top of Form

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|Which of the following statements about HT and cholesterol is correct? |

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|Oral estrogen raises total cholesterol. |

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|Transdermal estrogen raises triglyceride concentrations. |

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|HDL-raising effects of estrogen are dependent on route of administration and dose. |

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Bottom of Form

Ms. Sanchez also suffers from dyslipidemia and is taking rosuvastatin to control her cholesterol. You are once again challenged to describe how ET might affect her preexisting conditions. The effects of estrogen loss and/or therapy on lipid metabolism and on the vascular system are quite complex. In animal studies, 27-hydroxycholesterol is an oxysterol metabolite of cholesterol elevated in hypercholesterolemia and found in plaque (foam cells).[17] It is a competitive antagonist of estrogen-receptor action in the vasculature. It inhibits estrogen-dependent production of nitric oxide by vascular cells. It acts like an endogenous selective estrogen-receptor modulator in the loss of estrogen protection from vascular tissue. While it has been studied elegantly in animals as an important potential mechanistic reason why hormone effects can be both beneficial and detrimental depending upon the age and the health of the vascular system, relevance to humans is currently being investigated.

 

Atherogenesis is predicted by lipid trafficking. With endogenous estrogen waning during the menopause transition, lipid metabolism is altered. Endogenous mechanistic effects of estrogen on lipid metabolism are likely not the same as exogenous effects given orally. Estrogen increases apolipoprotein A1 (apoA1) production and inhibits hepatic lipase production, shifting HDL-C size. HDL-C levels increase with exogenous oral ET; however, it is unclear how this affects direct reverse cholesterol transport to remove plaque from arteries. Oral ET causes a shift of LDL-C size from large to small. Small LDL-C is less efficiently captured by LDL-C receptors for removal by the liver. There is induction of triglyceride-rich, very low-density lipoprotein assembly. Although circulating LDL-C levels are lowered, this is likely because of metabolism to more atherogenic, smaller LDL-C particles. Estrogen up-regulates LDL-C receptors in general. It remains unclear how the overall effects translate into more or less plaque deposition and stability with either endogenous estrogen or exogenous estrogen. RCTs are underway to address this issue.

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|Oral ET is more likely to precipitate pancreatitis in someone who has which of the following? |

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|Markedly elevated triglycerides |

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|Markedly elevated LDL-C |

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|Markedly elevated HDL-C |

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Both oral and transdermal ET have been shown to increase HDL-C and to decrease LDL-C. Significant hepatic stimulation with oral ET increases production of triglycerides, whereas transdermal ET has a more neutral effect on triglycerides. Oral ET taken by a woman with very elevated triglycerides can precipitate a pancreatitis.

Oral ET increases C-reactive protein, an inflammatory protein, while transdermal estrogen does not.[18] Oral ET increases total and HDL-C-associated serum amyloid A (SAA), another inflammatory protein, and it alters HDL-C composition to contain a higher SAA.[19] However, most experts believe that these inflammatory changes are hepatic-induced effects that are not necessarily detrimental to blood vessels and contributors to atherogenesis.

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|Which of the following statements best describes the relationship between ET and VTE risk? |

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|Oral ET has been associated with higher odds for VTE than transdermal ET. |

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|Data suggest that the risk of VTE when exogenous ET is prescribed by the transdermal route is equivalent to the risk when the same dose is |

|given orally. |

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|Women without factor V Leiden coagulation disorder who have a BMI ≤25 have been shown to have a greater risk of VTE. |

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With her high blood pressure and high cholesterol, Ms. Sanchez must be counseled on the cardiovascular-related risks or benefits of ET use. She comments during the counseling that her friend had mentioned that she quit ET over fear of VTE. She asks about VTE.

An increased risk of VTE with oral estrogens has been found in both observational studies and in RCTs.[20] Oral estrogens, in contrast to transdermal estrogens, appear to decrease the thrombin-inhibiting activity of activated protein C (APC); this may contribute to APC resistance.[21] Reduced activity of APC is thought to contribute to increased risks of cardiovascular events. Oral estrogen decreases antithrombin III (AT III), whereas transdermal estrogen appears to have fewer adverse effects. Reduced AT III activity is associated with a greater risk of VTE. Numerous studies have shown that transdermal estrogen, unlike oral estrogen, has fewer effects on fibrinogen, Factor VII, von Willebrand factor, and prothrombin fragments 1 and 2.[22]

Mechanistically, this may be why the case-control Estrogen and Thromboembolism Risk (ESTHER) study found that the odds of VTE using oral ET or EPT was 4.2 compared with 0.9 for transdermal ET. The combination of obesity with oral estrogen increased the odds of VTE. In this study, most current users of oral ET received estradiol, mean dose 1.5 mg/day, ranging from 0.5 to 2.0 mg daily. However, since VTE risk with oral ET is dose-dependent, low doses may in fact have little impact on increasing VTE risk. In the ESTHER study, having a factor V Leiden or other prothrombotic mutation and using oral ET increased the odds of a thrombosis dramatically; yet this multiplicative synergy was not seen with transdermal therapy.

Long-term prospective studies are needed to determine the safety of transdermal therapy with regards to VTE, particularly in women who are obese, have a genetic propensity for thrombosis, or have other risk factors for thrombosis. The case-control methodology is a useful design, though not definitive for exploring this question because, fortunately, VTE is rare when estrogen is used.

 

 

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|With respect to changes in sex hormone-binding globulin (SHBG) with ET, which of the following is true? |

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|Oral estrogen raises SHBG. |

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|Transdermal estrogen raises SHBG. |

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|Both oral estrogen and transdermal estrogen raise SHBG. |

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SHBG is synthesized in the liver and is partly responsible for controlling the amount of free testosterone in the blood, thereby aiding in the regulation of androgenic effects of testosterone production. When SHBG is in excess, this reduces free testosterone and is potentially associated with diminished libido. Oral estrogen and its metabolites increase SHBG. Transdermal estrogen has a small effect on SHBG and circulating free testosterone.

Ms. Sanchez is also at high risk for diabetes and is currently taking metformin. Any relationship between HT and diabetes and/or diabetes medication must be considered.

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|With respect to the effects of ET on diabetes, which of the following is true? |

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|Taking oral ET is associated with a lower risk of developing diabetes. |

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|Using transdermal ET has been shown to lower the risk of diabetes. |

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|Taking oral ET increases the risk of diabetes. |

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A comparison of the short-term effects of oral estrogen versus transdermal estradiol on C-reactive protein, other serum markers of inflammation, and other hepatic proteins in naturally menopausal women[23-24] pooled results of 107 trials. It showed that ET/EPT reduced abdominal fat (-6.8%), insulin resistance as measured by HOMA-IR (-12.9%), and new-onset diabetes (relative risk, 0.7) in women without diabetes. In women with diabetes, ET/EPT reduced fasting glucose (-11.5%) and HOMA-IR (-35.8%). ET/EPT also reduced LDL-C/HDL-C ratio (-15.7%), lipoprotein(a) (-25.0%), mean blood pressure (-1.7), E-selectin (-7.3%), fibrinogen (-5.5%) and plasminogen activator inhibitor-1 (-25.1%). Oral ET produced larger beneficial effects than transdermal agents, but increased C-reactive (37.6%) and decreased protein S (-8.6%), while transdermal agents had no effect.

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|With Ms. Sanchez's preexisting medical conditions, which of the following is the most likely preferred route of ET administration? |

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|Oral |

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|Transdermal |

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|Injectable |

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Ms. Sanchez understands that her hot flashes would most likely resolve over time without treatment, but believes that the potential benefits of low-dose ET would outweigh her potential risks. She accepts your recommendation of low-dose ET for short-term treatment. Because of her risk profile, you would like to recommend a transdermal ET.

All transdermal ET products available in the United States and Canada contain estradiol, bioidentical to the body's own estrogen. The clinical benefits of transdermal ET are applicable to all products, and all are government approved for treating moderate to severe vasomotor symptoms. Each product delivers a steady level of estradiol into the bloodstream, avoiding fluctuating hormone levels. The "standard" dose is 0.05 mg/day, although using the lowest effective dose is the clinical goal. A variety of application methods are available: transdermal patches, a transdermal gel, a transdermal spray, and a topical emulsion. (See the NAMS Web site for a complete list.) Differences in formulations and applications can influence patient acceptance. You explain the various options to Ms. Sanchez, along with the potential benefits, risks, and side effects she may experience with any systemic ET.

 

Transdermal patches.

 

The first technology used for the transdermal route of estrogen administration was a reservoir patch, constructed with a drug reservoir, a backing gel layer, and an alcohol-containing membrane to control the rate of drug release. This type of patch, still available in the United States and Canada, has been associated with rates of local irritation of up to 46%.[25] Adhesive or the alcohol solvent is generally thought to be responsible. This reservoir-type patch is applied twice weekly.

Newer matrix-type patches available in the United States and Canada include a solution or suspension within a polymer or textile pad held in contact with the skin; adhesive is only on the perimeter of the patch. This provides a more consistent delivery and is associated with less frequent skin reactions because of the absence of alcohol and the presence of air circulation to the skin. Some matrix patches require twice weekly application, whereas others are applied only once a week. A variety of strengths are available to tailor the dose to the patient, with the lowest-dose product delivering 0.014 mg/day. Different size patches are also available. They are often applied on the buttocks.

All transdermal patches are more convenient than other transdermal products, as they do not require daily application. Up to 10% of patches can fall or rub off, become dirty, or not be discreet.

 

Transdermal gels.

 

Transdermal gels were developed to overcome the local irritation problem with patches. Gels are applied to the inner forearm and dry quickly, but issues of washing, bathing, or inadvertently passing hormones onto others require that the user follow the instructions carefully. Some gel products are delivered via a metered pump whereas one gel comes in a packet. All require daily application. The lowest-dose option, available in the United States but not Canada, delivers 0.003 mg/day.

 

Transdermal spray.

 

  The latest advance in delivering transdermal ET is the transdermal spray. Available in the United States but not Canada, the product incorporates estradiol, octisalate, and alcohol in a metered-dose pump. When applied to the inner forearm, the alcohol dissolves through the stratum corneum and allows the estradiol and the octisalate to penetrate the top layer of the skin. When the alcohol evaporates, a depot of octisalate and estradiol remains. The octisalate facilitates slow absorption of estradiol through the epidermis into the dermis, where it reaches the circulation through capillaries. This regimen provides a 24-hour sustained release used once a day. Advantages include a quick drying process and no residue left on the skin. Skin irritation is uncommon. The risk of transfer to another person appears to be less than with gel preparations. Each 90 mcL spray delivers 0.021 mg estradiol. The label says up to 3-spray doses a day are allowed.

 

Topical emulsion.

 

One product available in the United States but not Canada is an emulsion of tiny particles of estradiol and soybean oil. Two packets applied daily (one packet to each thigh) deliver 0.05 mg estradiol. The unscented soy-based lotion is moisturizing. Skin irritation is uncommon.

Ms. Sanchez selects the transdermal option that is most appealing to her and agrees to a course of low-dose, short-term (2-3 years) therapy. After that time, she will stop therapy to see if she still needs to continue ET. She agrees to return for a follow-up visit, including reassessment of lab values, in 6 weeks.

Having patients adhere to the prescription plan is an ongoing challenge for any healthcare practitioner, and the ET plan is no exception. One survey from a managed care database found that close to 75% of women discontinued ET within 2 years of starting.[26] The primary reasons for stopping are uterine bleeding, breast tenderness, weight gain, and fear of cancer. Without a uterus, Ms. Sanchez will not have a concern with uterine bleeding or uterine cancer.

 

Conclusion

 

In recent years, there have been considerable advances in the technology of ET/EPT products and an improved understanding of appropriate doses and differences in routes of delivery. Transdermal approaches appear attractive because they have fewer metabolic disturbances, which may translate into fewer serious adverse effects, particularly for certain patient populations. Issues of efficacy for VMS relief, safety, cost, ease of use, and compliance will likely determine which of the many available options are most widely used by the majority of postmenopausal women with menopause-related symptoms. Studies addressing safety of long-term ET use of any of the newer options are of keen interest.

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References

References

1. Williams RE, Kalilani L, DiBenedetti DB, et al. Frequency and severity of vasomotor symptoms among peri- and postmenopausal women in the United States. Climacteric. 2008;11:32-43.

2. The North American Menopause Society. Treatment of menopause-associated vasomotor symptoms: position statement of The North American Menopause Society. Menopause. 2004;11:11-33.

3. Gold EB, Sternfeld B, Kelsey JL, et al. Relation of demographic and lifestyle factors to symptoms in a multi-racial/ethnic population of women 40-55 years of age. Am J Epidemiol. 2000;152:463-473.

4. Brinton EA, Hodis HN, Merriam GR, Harman SM, Naftolin F. Can menopausal hormone therapy prevent coronary heart disease? Trends Endocrinol Metab. 2008;19:206-212.

5. Salpeter SR, Walsh JM, Greyber E, Salpeter EE. Brief report: Coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med. 2006;21:363-366.

6. Balfour JA, Heel RC. Transdermal estradiol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints. Drugs. 1990;40:561-582.

7. Campagnoli C, Biglia N, Altare F, et al. Differential effects of oral conjugated estrogens and transdermal estradiol on insulin-like growth factor 1, growth hormone and sex hormone binding globulin serum levels. Gynecol Endocrinol. 1993;7:251-258.

8. Bachmann GA, Schaefers M, Uddin A, Utian WH. Lowest effective transdermal 17beta-estradiol dose for relief of hot flushes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2007;110:771-779.

9. Gadomska H, Barcz E, Cyganek A, Leocmach Y, Chadha-Boreham H, Marianowski L. Efficacy and tolerability of low-dose transdermal estrogen (Oesclim) in the treatment of menopausal symptoms. Curr Med Res Opin. 2002;8:97-102.

10. Rozenberg S, Ylikorkala O, Arrenbrecht S. Comparison of continuous and sequential transdermal progestogen with sequential oral progestogen in postmenopausal women using continuous transdermal estrogen: vasomotor symptoms, bleeding patterns, and serum lipids. Int J Fertil Womens Med. 1997;42(Suppl 2):3763-3787.

11. Buster JE, Koltun WD, Pascual ML, Day WW, Peterson C. Low-dose estradiol spray to treat vasomotor symptoms: a randomized controlled trial. Obstet Gynecol. 2008;111:1343-1351.

12. Endrikat J, Graeser T, Mellinger U, Ertan K, Holz C. A multicenter, prospective, randomized, double-blind, placebo-controlled study to investigate the efficacy of a continuous-combined hormone therapy preparation containing 1 mg estradiol valerate/2 mg dienogest on hot flushes in postmenopausal women. Maturitas. 2007;58:201-207.

13. Panay N, Ylikorkala O, Archer DF, Gut R, Lang E. Ultra-low-dose estradiol and norethisterone acetate: effective menopausal symptom relief. Climacteric. 2007;10:120-131.

14. Speroff L, Haney AF, Gilbert RD, Ellman H. Efficacy of a new, oral estradiol acetate formulation for relief of menopause symptoms. Menopause. 2006;13:442-450.

15. Rowan JP, Simon JA, Speroff L, Ellman H. Effects of low-dose norethindrone acetate plus ethinyl estradiol (0.5 mg/2.5 μg) in women with postmenopausal symptoms: updated analysis of three randomized, controlled trials. Clin Ther. 2006;28:921-932.

16. Palacios S. Pulsed estrogen therapy: relieving climacteric symptoms, preventing postmenopausal bone loss. Climacteric. 2002;5(Suppl 2):32-39.

17. Umetani M, Domoto H, Gormley AK, et al. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat Med. 2007;13:1185-1192.

18. Kawano H, Yasue H, Hirai N, et al. Effects of transdermal and oral estrogen supplementation on endothelial function, inflammation and cellular redox state. Int J Clin Pharmacol Ther. 2003;41:346-453.

19. Abbas A, Fadel PJ, Wang Z, Arbique D, Jialal I, Vongpatanasin W. Contrasting effects of oral versus transdermal estrogen on serum amyloid A (SAA) and high-density lipoprotein-SAA in postmenopausal women. Arterioscler Thromb Vasc Biol. 2004;24:e164-e167.

20. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336:1227-1231.

21. Scarabin PY, Oger E, Plu-Bureau G. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428-432.

22. Menon DV, Vongpatanasin W. Effects of transdermal estrogen replacement therapy on cardiovascular risk factors. Treat Endocrinol. 2006;5:37-51.

23. Shifren JL, Rifai N, Desindes S, McIlwain M, Doros G, Mazer NA. A comparison of the short-term effects of oral conjugated equine estrogens versus transdermal estradiol on C-reactive protein, other serum markers of inflammation, and other hepatic proteins in naturally menopausal women. J Clin Endocrinol Metab. 2008;93:1702-1710.

24. Salpeter SR, Walsh JM, Ormiston TM, Greyber E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab. 2006;8:538-554.

25. Samsioe G. Transdermal hormone therapy: gels and patches. Climacteric. 2004;7:347-356.

26. Kayser J, Ettinger B, Pressman A. Postmenopausal hormonal support: discontinuation of raloxifene versus estrogen. Menopause. 2001;8:328-332.

Authors and Disclosures

The content and views presented in this educational activity are those of the faculty and do not necessarily reflect those of The North American Menopause Society (NAMS), Ther-Rx Corporation, or Medscape. This material is prepared based on a review of multiple sources of information, but is not exhaustive of the subject matter. Therefore, prior to making clinical decisions about individual patients, healthcare providers should review and consider other material.

 

Author

Robert A. Wild, MD, PhD, MPH

|Professor of Reproductive Endocrinology, Adjunct Professor of Biostatistics and Epidemiology, Adjunct Professor of Medicine |

|(Cardiology), Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma |

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