Hormone replacement therapy (HRT) is supplementing women with hormones lost during the menopausal transition. To relieve the symptoms associated with menopause, conventional HRT includes an estrogen and progesterone component to mimic hormones created by the human ovary.

Estrogen therapies are numerous, and include those indigenous to the human ovary, for example, estradiol and estriol. Other estrogenic compounds include conjugated equine estrogen (CEE), the most commonly prescribed estrogen in the United States. They are not identical in their effect on the human body but share the same FDA indications, according to the Physicians Desk Reference.[1][2][3] The indications for menopausal issues include:

• Treatment of vasomotor symptoms of menopause
• Treatment of genitourinary syndrome of menopause ( previously known as vaginal and vulvar atrophy)
• Prevention of osteoporosis

A progestogen is a term used to include not only progesterone made by the human ovary but also progesterone-like substances, also known as progestins. A woman who desires HRT and has an intact uterus must have a progestogen with estrogen to protect her uterus from endometrial hyperplasia or malignancy. Estrogen alone will cause the endometrial lining to grow. Progestogens stabilize the lining from proliferating abnormally. It is assumed that if a woman has had a hysterectomy that she no longer needs a progestin. Progesterone, however, is different as it can provide symptom relief from sleep disturbance and mood instability, and increasing evidence support that it offers tissue protection to the breast.[4][5][6]

FDA-approved indications for progestogens include:

•  Amenorrhea, either primary or secondary
•  Assisted reproductive technology treatment
•  Endometrial hyperplasia
•  Dysfunctional uterine bleeding

There are numerous estrogen and progestogen choices, and they may be administrated orally or transdermally either through cream, patch, vaginal inserts, or subdermal pellets. Each route of administration has unique benefits and risks.

Oral Estrogen: Any estrogen administered orally results in increased activated protein-C resistance, increasing the risk of a blood clot. Oral estradiol also induces the hepatic formation of matrix metalloprotease 9, which decreases the formation and rupture of atherosclerotic plaque.

Transdermal Estrogen: Bypasses the hepatic metabolism that produces activated protein-C resistance, and the risk for blood clotting is negated.

Progestin administration is usually via the oral route, although a few are available in combination with estrogen in patch forms. Progesterone is available in an oral form that can also be used vaginally for non-FDA-approved uses.

Specialized pharmacies make compounded estrogen and progesterone creams, sublingual troches, and vaginal inserts, but these are not FDA approved and are not be included in this article.

When studying the potential adverse effects of HRT, the most referenced information in the United States comes from the Women's Health Initiative (WHI).[7][8][9]

WHI Trial

This was a multifaceted trial, including two double-blind, placebo-controlled, randomized trials of postmenopausal hormone therapy.

The first arm included CEE at 0.625 mg per day with medroxyprogesterone acetate (MPA) 2.5 mg per day. The second arm studied patients who had prior hysterectomies and treated with CEE 0.625 mg only.

HRT and the Breast

The CEE/MPA arm was discontinued earlier than expected due to an increased incidence of invasive breast cancer of 24% (HR=1.24). The CEE only arm was not discontinued early, completed in 2004, and extended follow up of patients has continued for 11.8 years. CEE use for 5 to 9 years is associated with a statistically significant reduction in breast cancer by 23% (HR=0.77). Those in the CEE arm also had decreased mortality from breast cancer by 63% compared to those not on CEE, and 38% fewer died from all other causes after breast cancer was diagnosed.

When examining evidence from European studies which usually use estradiol derivatives rather than CEE, and non-MPA progesterone or progestins, the conclusions are vastly different and unequal. Transdermal estradiol alone increased the risk of breast cancer by 10%, but estradiol with progesterone decreased the risk of breast cancer by 10%.

HRT and the Heart

In the WHI CEE/MPA arm, the overall incidence of coronary heart disease (CHD) increased by 24% over five years of use, with the most substantial elevation in risk within the first year, with an increase of 81% (HR=1.81). This evidence requires cautious interpretation due to the following:

• The average age of the patient treated in this study was 62 years. In women who started on therapy within ten years of menopause, there was a risk reduction of CAD of 11% (HR=0.89), but this was not statistically significant.
• In those women who continued CEE/MPA for over six years, the risk of CAD dropped by 30% (HR=0.70).

These risks do not apply to estradiol and progesterone based treatments. Basic science studies show several mechanisms through which estradiol (not CEE) is cardioprotective. These include stabilization of atherosclerotic plaques, reduction of carotid intima-media thickness (CIMT), and decreasing coronary artery calcium (CAC) scores. Numerous subsequent studies both in Europe and the United States show that cardiovascular disease and death are prominently reduced when HRT commences within the first four years of the menopause transition. The "Timing Hypothesis" refers to the theory that when starting HRT closer to the time of the menopause transition, a cardiovascular benefit is seen compared with later initiation.

HRT and Risk of Stroke

Stroke incidence increased in both arms of the WHI trial by 31% in the CEE/MPA arm, and 39% in the CEE arm.

Studies using oral estradiol are conflicted, showing a similar stroke risk, but the incidence of fatal stroke is unchanged.

HRT and the Risk of Venous Thromboembolism (VTE)

VTE, comprised of deep venous thrombosis and pulmonary embolism, was increased by 2-fold (HR= 2.06) in the WHI CEE/MPA arm.

Transdermal estradiol does not confer the same thromboembolic risk, as is evidenced by numerous European studies. The ESTHER study from France showed an overall risk of 0.9 for a blood clot, which is a decreased risk. Subsequent studies looking at other transdermal estradiol doses and routes confirm these findings, with at least a null effect for blood-clotting risk.

Contraindications for oral or transdermal estrogen-based therapies include:

• Known, suspected or history of breast cancer
• Known or suspected history of other estrogen-based cancer, i.e., uterine cancer. Women who have had a hysterectomy and have no remaining evidence of disease are still candidates for HRT
• Active deep venous thrombosis (DVT) or a history of DVT or pulmonary embolism (PE)
• History of blood clotting disorder, the most common being Factor V Leiden mutation carriers
• Active or history of arterial thrombotic diseases such as myocardial infarction or stroke
• Chronic liver disease or dysfunction

These contraindications do not apply to transvaginal based estrogen therapies, as the serum concentration of estrogen from this route is extremely low. The North American Menopause Society (NAMS) has recommended that the black-box warning that applies to conventional HRT not be applied to transvaginal estrogen treatments.