If any clear message has emerged from the scientific and media frenzy set off by the cessation of the Prempro arm of the Women’s Health Initiative, it is that menopause is hardly a simple, clear-cut phenomenon.

American women and the physicians who treat them are coming to realize there is no easy, one-size-fits-all strategy for managing menopause that guarantees symptom relief, long-term systemic benefits and complete freedom from risk. The experience of menopause and the risks associated with it are highly individualized. The “right” approach must be found one woman at a time.

“This is wonderful work to be doing. It is not cut and dry. It is about helping women clarify what they need to feel good, identifying these needs and expectations, and working together to achieve them. So long as you don’t try to give people the ‘Answer,’ this is a great time to be practicing,” said Marie Annette Brown, PhD, professor of nursing, University of Washington.

Dr. Brown has reservations about patients on HRT stopping cold in a fit of post-Prempro angst. In some cases, there may be strong reasons for wanting to stop, but cold-turkey is not the way to do it. Any sudden change in hormone levels will produce major physiologic ripples that are not going to be pleasant or healthy. If a woman wants to discontinue, it is best to taper off.

Subtypes of Menopause

Technically, menopause is defined as a full 12-months without a menstrual period. The changes a woman feels on the way are highly variable. So must the treatment be. Many women’s health experts believe it is the failure to recognize individual variance that led to much of the current confusion and anger.

Dr. Brown believes there are likely 4 or 5 distinct patterns of menopausal transition. For example, some women have heavy symptoms during their mid-40s perimenopausal stage. By the time they reach the menopausal threshold, they are relatively asymptomatic. Others have an asymptomatic prelude, followed by progressive increases in symptom severity. Some have fairly discrete transitions, while others may have disruptive symptoms all through their 50s and even into their early 60s.

Thin women may actually have more extreme symptoms compared with heavy-set women for the simple reason that estrogen is fat-soluble. Women with less body fat will have less stored estrogen. When ovarian production stops, they may experience the crash more acutely. On the other hand, those with less body fat have lower overall risk of cardiovascular disease.

Perpetual State of Lactation

Endocrinologically, menopause is like being in a state of lactation forever, according to Ricki Pollycove, MD, an ob.gyn. at the University of California, San Francisco. After a woman delivers a child, estrogen falls off precipitously, while lactation stimulates prolactin release. The prolactin surge shuts down ovarian estrogen and progesterone production until the woman stops nursing.

Physiologically, these hormonal changes mobilize calcium from bone, and lipids from fat stores, both of which go to enrich breast milk. Once she finishes lactation, estrogen and progesterone production resume, normal cycling is restored, calcium is re-deposited in bone, and circulating lipids decline.

The estrogen fall-off during menopause induces similar changes—skeletal calcium resorption and increased circulating lipids—only these compounds are not used for breast milk. Calcium is simply lost, and the lipids may end up in the vessel walls. Since this process is never turned off after menopause, this metabolic state persists unless the woman starts HRT in some form.

Dr. Pollycove stressed it was only very recently that the majority of women began to live for decades after menopause. Human endocrine physiology is not really set up for that. “When a patient asks me what is the natural history of menopause, my short answer could be, ‘Probably to be dead already.'”

Genetic factors, body type, dietary and lifestyle factors, ethnic or racial differences, and cultural assumptions all influence a particular patient’s menopausal experience. And these must be the guideposts for treatment.

While Dr. Pollicove acknowledged the significance of the cancer, stroke and deep vein thrombosis risk associated with long-term Prempro, she and many other gynecologists quickly point out there is still a very strong rationale for HRT. Low estrogen level is a risk factor for many physical and psycho-emotional disorders. Prempro, which many doctors found problematic even before WHI, simply may not be the best solution for many women.

Estrogen Metabolism Governs Risk

“The big issue missed by many people interpreting WHI is that evaluations of estrogen related risk must consider active forms of estrogen, both endogenous and from HRT, in relation to the levels of estrogen metabolites which are ‘antiestrogenic’ and protective,” said Michael Zeligs, MD, a leading researcher into the use of phytoestrogens for cancer protection. “The formation and balance of estrogen metabolites—particularly the 2-hydroxy estrogens versus cancer-promoting 16-hydroxy estrogens—is what determines a given individual’s response to HRT and the risk of cancer and thrombosis.”

Dr. Zeligs stressed that the cancer-preventive, antioxidant 2-hydroxy metabolite can only be produced from estradiol. Conjugated equine estrogens (CEE) that constitute Premarin cannot be converted into the 2-hydroxy metabolite. In fact, one of the horse estrogens in Premarin (4-hydroxyequilenin) may increase breast cancer risk. There are also studies suggesting that synthetic progestins like Provera impair metabolism of estrogen to the more beneficial metabolites.

How a patient will respond to HRT has a lot to do with how she metabolized estrogen in her premenopausal life. Those who overproduce the inflammatory 16-hydroxy metabolite are at higher risk of adverse events from HRT.

Fortunately, this metabolic predisposition can be largely rectified through regular consumption of cruciferous vegetables (broccoli, cabbage, etc.), or daily supplementation with 50–100 mg diindolylmethane (DIM) a compound derived from crucifers that shifts metabolism in favor of the beneficial 2-hydroxy metabolite. (Bioavailable DIM is marketed by BioResponse. For more information, visit: www.bioresponse.com.)

Treat Intentionally

The bottom line with HRT is, know clearly why you are giving it to each patient, said Tori Hudson, ND, Program Director of the Institute of Women’s Health and Integrative Medicine, and a professor of medicine at both Bastyr University and National College of Naturopathic Medicine. Whether you and your patient choose to use pharmaceutical hormones, bioidentical “natural” hormones, or phytoestrogens, you both should know what you are trying to do and why. “Don’t just give hormones because someday, somehow it might help.”

Based on existing science, the only solid indication for HRT is relief of menopausal symptoms. In most cases this should only be used for a relatively short-term period of 4–5 years. Indefinite HRT is not really supportable by science, and there are many other ways to deal with the risks of osteoporosis, depression and cardiovascular disease, Dr. Hudson said in a presentation at the annual meeting of the American Association of Naturopathic Physicians.

If you choose to prescribe HRT, go with phytoestrogens or one of the many bioidentical estrogen products. CEE is out, Dr. Hudson stressed. “I think a non-bioidentical mixture of (equine) hormones is creating problems at the steroid receptor level. Compounds within Premarin look familiar enough to the receptors to enable binding. But there are all these compounds which variably influence genetic expression. It’s like having chronic low level toxins binding to our receptors.”

She believes progestin may prove to be the big bugbear in HRT, not estrogen. “Progestin is probably protective of the ovary, but not so good for the heart or breast.” This certainly seems true for the synthetic medroxyprogesterone acetate in Prempro. “Synthetic progestins cause coronary artery spasm while naturally occurring progesterones do not,” Dr. Hudson said. However, she acknowledged that far more research is needed on natural progesterones before declaring them unequivocally safe. Erring on the side of caution, she recommends using natural progesterones only for short-term symptom relief.