In this third and final installment to our series, we'll outline the various modalities of hormone replacement therapy (HRT), briefly examine the biochemistry of HRT, and outline the alternatives for managing menopausal effects in the short and long term.

What, exactly, is being replaced?

When we talk about endogenous estrogen (meaning estrogen produced naturally in the body) we're really talking about three unique versions of the hormone manufactured from cholesterol in the ovaries and in body fat. All three of these estrogens fit the estrogen receptors, sites of hormonal action in the body, but they vary in strength and action. Estradiol is the most potent endogenous estrogen and the predominant estrogen "operating" in non-pregnant premenopausal women. Estrone is the major estrogen produced by a woman's body after menopause. Estriol is the dominant estrogen during pregnancy. Estradiol can be converted into estrone, and estrone can be converted into estradiol.

The body produces only one form of progesterone, almost all of it by the follicle in the ovary after it releases an egg. At this stage the follicle is called the corpus luteum. A small amount of progesterone is produced by the adrenal gland, but most of that is mainly used to make other hormones. Postmenopausal progesterone production is virtually nonexistent.

Estrogen, progestin, or both?

HRT uses processed or synthesized hormones to augment declining natural production of estrogen and progesterone in peri- and postmenopausal women. HRT may mean taking an estrogen, a progestin (a substitute progesterone), or a combination of the two. Technically speaking, 'hormone replacement' also refers to the therapeutic use of testosterone, since women do produce testosterone, and its production declines after menopause, but we'll save the subject of testosterone replacement therapy for a separate article.

As a rule, estrogen-only HRT is not used in women who still have their uterus because estrogen stimulates growth of the uterine lining (endometrium), and this growth can get out of control and develop into endometrial cancer. The addition of a progestin counters the added risk of endometrial cancer. However, some women with an intact uterus simply cannot tolerate progestin therapy because of side effects-often increased anxiety and depression. These women may opt for estrogen-only HRT, but they must understand that this is not standard medical practice and that they will require an endometrial biopsy once a year and/or an ultrasound measurement of endometrial thickness. They also need to realize that the endometrial-cancer risk of unopposed estrogen therapy persists long after therapy is discontinued and that the need for an annual endometrial biopsy will continue for another 10 to 15 years.

Combination HRT

Two modes of combination HRT are possible: cyclical and continuous. Cyclical therapy employs a daily dose of estrogen with a progestin added for a few days each month. The addition of progestin mimics the natural function of progesterone: a menstrual period follows after progestin administration ceases.

Many women don't care for the return of menstrual periods, however, and may opt for continuous therapy, in which estrogen and progestin are both taken daily. The concept is to prescribe a progestin dose that's sufficient to protect against endometrial cancer but modest enough so that it will not cause monthly bleeding. However, between 60% and 70% of women who start continuous HRT experience breakthrough bleeding and spotting. Postmenopausal breakthrough bleeding and spotting are symptoms of endometrial cancer, and if such bleeding persists beyond six months, an endometrial biopsy or dilation and curretage (D&C) will be needed to rule out cancer.

Most women who choose continuous HRT will require an average of three endometrial biopsies, and some women on continuous HRT, despite the lower progestin dose, still have regular menstrual periods for up to a year, even after the breakthrough bleeding and spotting stop. Bleeding irregularities are the most common reason women discontinue HRT. Progestin-dose modification may help eliminate these unwanted effects of HRT.

The variety of replacement hormones

The subject of hormone replacement is rife with controversy, extending even to the nomenclature used to describe the hormones themselves. Take the term natural, for instance. Many commentators regard the estrogen in Premarin--the most widely prescribed estrogen replacement product in the U.S.--as a natural product. It is, in fact, harvested from the urine of pregnant horses. (Some writers on menopause have remarked that the conjugated equine estrogen in Premarin is "natural" only if you happen to live in a barn and eat hay.) The equine estrogen in Premarin is converted to estradiol and estrone by metabolic processes in the body.

Christiane Northrup, MD, a widely read contemporary menopause expert, champions the use of bioidentical hormones. These are synthesized from hormonal building blocks found in such plants as yams and soybeans. They are designed to be exact structural matches for endogenous hormones. Then there are direct plant sources of estrogen (Black Cohosh, soy isoflavones, lignans) and progestin (Chaste Berry, Wild Yam). Wulf Utian, MD, and Ruth Jacobowitz list 12 different forms of "natural" replacement estrogen in their book Managing Your Menopause (Prentice-Hall).

A discussion of the relative merits of the various hormone formulations is beyond the scope of this article. Our only point here is to alert you to the wide range of choices. If you are considering starting HRT, these are choices best made in consultation with a sympathetic physician trained and experienced in menopause management.

An even wider variety of dosage forms

Estrogen can be administered orally (pill), by injection, transdermally (with a patch device), topically (in the forms of creams, gels, and vaginal inserts), or by a subdermal implant. Progestin can be delivered orally (pill), transdermally (patch), topically (cream), by subdermal implant (under the skin), or via a progestin-releasing IUD. There are scores of HRT products on the market today employing the full range of available replacement hormones. Dr. Susan Love's Hormone Book lists, for example, 34 different progesterone creams, alone. But having a wide variety of choices available improves the chances, for any given woman, of finding a formulation and delivery system that confers maximal benefit without significant side effects.

Alternative approaches to managing menopause

The pharmaceutical "culture" is a strong influence in this country. We tend to like the idea of simply taking a pill to cure or correct our mental and physical ailments. There is no question that HRT can be of tremendous benefit to many women when it comes to managing some of the "symptoms" of perimenopause and some of the long-term postmenopausal effects of diminished estrogen production. Many experts believe, for example, that long-term HRT helps prevent coronary artery disease and reduces the risk of heart attack. But is also a proven medical fact that lifestyle changes such as quitting smoking, getting sufficient aerobic exercise, and following a "heart-smart" diet high in fiber and low in saturated fat can have similar effects. The most common symptom of perimenopause and the one that most often drives women to seek medical help is hot flashes. Hot flashes generally respond very well to HRT, but there are also herbal remedies such as Black Cohosh that are of proven value in the treatment of hot flashes, and there are nonpharmaceutical interventions such as acupuncture, meditation, exercise, biofeedback, vitamin E supplements, eating soy protein, and reducing stress that have been used by many women to help control this troublesome symptom.