Individualizing Hormone Supplementation / Replacement Therapy

Despite the fact that we have more therapeutic options for menopausal patients than ever before, initiation and compliance with hormone replacement therapy (HRT) remains extremely low. It is estimated that only 17 percent of American women for whom HRT is appropriate are actually taking it and these rates of use are even lower among women of color and of lower socioeconomic status. The atmosphere of consumer mistrust of the pharmaceutical industry and inflated fears regarding breast cancer and its possible relationship to HRT incline millions of women not to seek any doctor-prescribed hormones in menopause. Conflicting reports in the medical literature, an inability to guarantee any woman that she will not get cancer and the potential threats of future litigation may also predispose doctors to de-emphasize the prescribing of HRT. For physicians it is helpful to frame this discussion with information gained from evolutionary biology, the current state of medical literature, awareness of media hype, “politically correct” thinking about menopause, patient expectations and individualization of therapy options. We can then assist our patients in making a positive health-promoting as opposed to a fear-based decision regarding HRT for relief of symptoms and/or long term disease risk reduction.
Increasingly the public demand for “natural” management of menopause begs the question, “What is natural in menopause?” From an evolutionary biological perspective one might shudder to learn that there is only one primate (a chimpanzee) and one bird that live more than a few months after cessation of fertile capacity. Most animals have died before they lose their reproductive capacity. I ask my patients to consider that the “natural” condition for menopause is probably to be deceased already. As unpopular as this thought may be it does give one pause to reflect upon one’s prior use of medical scientific advances to enhance survival and quality of life. The previous administration of antibiotics for a severe urinary tract infection, pneumonia or the injection of powerful prostaglandins to prevent post-partum hemorrhage may have allowed this individual woman we are caring for to experience the challenge of menopause. So why leave intellectual advances behind just when the going gets tough?
If one looks critically at the basics of the hormonal milieu and physiology of menopause, striking similarities exist between the low estrogen state of post partum lactation and the hypoestrogenemia of menopause. For very different biologic reasons the physiology is nearly the same: mobilization of fat from fat stores (to enrich the milk for offspring during lactation), and mobilization of calcium from bones (to enhance the healthy growth of nursing offspring). If there is no “decanting” of these precious elements via lactation they circulate in women’s vessels to contribute toward unfavorable lipid profiles with an increased risk for coronary heart disease and accelerated bone loss (increased reabsorption of bone and elevated urinary excretion of calcium). From an evolutionary biologic perspective, the healthiest older individuals may be those with endogenous high estrogen production, those who have a genetic predisposition to denser bones, lower blood pressure, optimal lipid ratios, who also maintain an active vigorous life style.
For the large majority of our patients (at least 80 percent) low rates of use of HRT are particularly lamentable given what we now know about the potential benefits of this therapy for short-term symptom control and long-term disease prevention. Healthy People 2000, the American College of Obstetrics and Gynecology, and virtually all other primary care expert bodies advise considering HRT for every woman at menopause. Few women fear heart disease although it inflicts significant loss of quality of life for most women and is the proximate cause of death for the large majority. As increasing data associate HRT use with significant reduction in risk for Alzheimer’s and other dementias, this has become a more powerful motivating force toward taking HRT, as well as improving life style (diet, exercise and smoking cessation). Fear of loss of independence with advancing osteoporosis, fractures and disability also motivates many women to seek medical care at mid life. Viewing both the individual and public health, HRT use in general should be increased.
A large part of the means by which we can make this happen lies in individualization, in recognizing that a one-size-fits-all approach will no longer suffice for our patients and that both evaluation and treatment must be tailored to each individual woman.

Individualizing the Evaluation

Listen and Share Information
Menopause marks the end of a period of relatively rapid change for women. To separate normal healthy aging changes from reproductive hormonal changes is an important feature of symptom assessment. Understanding the individual life goals for the menopause years is a great aid in designing a regimen that addresses each woman’s needs. How she prioritizes her health concerns is critical in designing a plan for a patient’s optimal health over the short and long term. I developed a simple one page questionnaire which quickly identifies a woman’s belief system, medical history and personal concerns. It is very helpful to separate short-term control of severe menopausal symptoms (usually requiring estrogen or other supplementation for only for 3 to 9 months) from long-term disease risk reduction and quality-of-life enhancing strategies. Fears about cancer lurk behind many discussions and should be articulated and discussed.

Dealing with the Fear of Cancer

Fear of breast cancer causes many women to refuse to initiate or to continue HRT. In fact the association between HRT and breast cancer risk is largely theoretical and has not been convincingly proven. Three thousand women have to take estrogen for 10 years to observe 1 excess case of breast cancer by meta-analysis data. Emotions run high when we discuss such grim numbers for this unfortunately high-incidence disease. Many women are alarmed by breast tenderness when HRT is initiated as most are unaware that the breast is an estrogen sensitive tissue. An open discussion of what is currently known about the association between hormone use and breast cancer risk proves reassuring. There are also very reassuring data regarding the use of ERT in menopausal women with previous local breast cancer, though it may be heresy to mention such iconoclastic concepts.(1)
The ability to provide a detailed individual assessment of breast cancer risk is now available to clinicians and should be strongly encouraged. High anxiety may be addressed with a referral to a genetic counselor. (In our community Patricia Kelley, PhD, is superbly knowledgeable and helps patients understand the larger concept of what risk really means. She can be reached at 415/353-6119.) Looking at such consults in terms of psychotherapeutic benefit places the discretionary dollars spent in a very reasonable range. The benefit-risk ratio must always be calculated for the individual, with educational referrals for breast self exam (BSE) often aiding women in making a positive as opposed to a fear-based decision regarding HRT.

Quality of Life Concerns

Quality of life concerns, short and long term, may require some gentle probing. Complaints about hot flashes and night sweats are offered freely. Frequently women don’t want to complain about depressive symptomatology as they may view depression as a personal failing. Few women initiate a dialogue about sexual concerns but most will respond openly when asked by their physician. Sleep problems are common complaints during both perimenopause and menopause, often further disrupted by vasomotor symptoms. Hormonal changes may not be solely responsible for sleep disorders (anxiety, family and/or financial stress are frequent contributors) but supplementation with low-dose estrogen approaches 85 percent success rates for achieving better sleep as well as ending hot flashes, both day and night (95 percent success with adequate HRT).

Breakthrough Bleeding

Abnormal bleeding history needs to be carefully addressed as this age group of women is at higher risk for endometrial overgrowth states (from hyperplasia to adenocarcinoma). Women with abnormal bleeding require a gynecology consult for optimal management, thus preventing more dysfunctional uterine bleeding and aiding with early detection of cancer. Virtually every study that has examined reasons for HRT non-adherence has found that bleeding is the biggest barrier (breast tenderness is number two). Breakthrough bleeding is the chief drawback of HRT for most women as it is at least a laundry problem and, worse, increases cancer fear. It is important to assess each individual patient’s feelings about bleeding and then, for those who would consider it a barrier to HRT use, endeavor to provide a regimen that avoids cyclic endometrial withdrawal and preferably achieves amenorrhea.

What to Look For

Body image issues (weight gain, central obesity, dry skin, poorly lubricated and inelastic vaginal tissues, ptotic breasts) are common fears and dismaying observations for many women as they age. Research studies confirm slight weight loss and favorable waist-hip ratios in HRT users as compared to non-users over 3 to 5 years (contrary to the myth that estrogen causes weight gain post-menopausally). When considering HRT we must be realistic in our assessment and optimistic in terms of functional support. For vaginal dryness complaints many non-pharmacologic products can assist with lubrication but estrogen delivered to atrophying tissues is still the most successful for symptom relief and urogenital function. A complete physical exam, with a detailed clinical breast exam, pap test, and stool occult blood screen, are the minimum for the perimenopausal/menopausal patient before initiating HRT. Well-tolerated endometrial sampling techniques, when indicated, are easily performed in almost all patients in the gynecology office. With a few additional lab tests we are ready to derive a treatment plan, individualized according to each woman’s needs.

Risk Assessment

Heart disease: Cholesterol fractionation, CBC are the principal tests in generally healthy women.
Osteoporosis: Bone mineral density, hip and spine, guide us with individual risk assessment for osteoporosis. Heel ultrasound may also be used to avoid the cost of a Dexa scan.
Breast Cancer: Family history (first degree relatives are most important), annual screening mammogram and clinical breast exam help to reassure the patient that she is free of abnormalities as best we can determine with current technology. A past history of benign breast disease is not a contraindication for HRT.
Uterine pathology: Endometrial sampling to evaluate abnormal bleeding and/or transvaginal sonogram may help to assess the uterine anatomy, endometrial thickness and possible intracavitary polyps and myomata uteri.
Other metabolic disease: Consider thyroid disorders as well as aberrant glucose metabolism, other less common endocrinopathies and evaluate baseline liver function tests and CBC.
Life Style: Emphasis on personal practice (smoking cessation, exercise, nutrition) is crucial.

Collaborate with the Patient

Sharing information builds an atmosphere of trust. After laboratory data and screening tests return, a repeat visit to review concerns, physical findings and medical history, helps women feel confident about their HRT choice. Written notes as topics are discussed, with a copy given to the patient, aid in recall of the process by which decisions were made. This serves to re-enforce your thoughtful discussion after the patient has long since left the office and provides documentation of her informed choice.

Tailoring Treatments for Patients

Perimenopause is characterized by hormone levels that are “irregularly irregular,” This can contribute to wide swings of emotions, often exacerbating underlying depressive disorders. Measuring levels of estradiol or follicle-stimulating hormone (FSH) at a single point in time may be misleading as the levels can rise and fall. Perimenopause can be diagnosed in any woman in the age range of approximately 40 to 55 years in whom regular cycling has transitioned to a pattern of irregular cycling (very short or very long intervals between menses) and finally amenorrhea.
Control of dysfunctional bleeding is the primary therapeutic goal in many women during this period. Progestogens (synthetic are best for controlling irregular ovulation) should be offered for bleeding complaints and may prevent serious blood loss causing anemia as well as endometrial hyperplasia. Generally progestins are used along with estrogen to both control bleeding and abolish menopausal symptoms with the combination of hormones. Newer preparations are available that have either continuous combined estrogen/progestin or three-day alternating cyclic estrogen/progestin.
For many nonsmoking perimenopausal women (without other absolute contraindications) low-dose oral contraceptives may provide the ideal therapy for this purpose. Low-dose OCs reduce the hypoestrogenic symptoms of perimenopause (such as hot flashes), and provide contraception (no “change of life” babies) and long term protection from ovarian cancer. Some women become intolerably symptomatic during the pill-free week and a very low-dose (25 mcg) estrogen transdermal patch or continuous use (hormone-containing pill every day) can be very successful. Within the confines of long term safety, openness to trying different hormone regimens adds flexibility and enhances confidence. Menopause, 12 months of amenorrhea with an FSH greater than 50, is more predictable than perimenopause. The threats of erratic ovulation and unintended pregnancy have passed. Thus treatment options differ slightly, focusing more on long term symptom control and risk reduction at the lowest possible doses of hormones. Combined continuous or cyclic use of progestins are the most common regimens today.
Natural and bioidentical hormones (estradiol, progesterone) come in a variety of preparations. The transdermal estradiol patch is preferred for some women while others dislike the “mark of menopause” displayed on their skin. Micronization of oral progesterone achieves better serum levels for more effective opposition of estrogen effects on the endometrium. Calibrated delivery systems of progesterone gel allows for more reliable administration of transcutaneous progesterone for the patient in whom this is desired. Except for women with a significant past history of endometriosis, long-term HRT regimens post-hysterectomy are simply estrogen, as there is no risk of endometrial overgrowth. There is an elevated risk for stimulation of endometriosis implants with long-term ERT, thus progestin opposition should be considered. Many synthetic estrogen-progestin combinations are available and have been successfully marketed for many years, though increasingly women request bioidentical HRT products first.
It is important to validate the perimenopausal/menopausal woman’s symptoms and reinforce that they are both normal and temporary. This often overlooked intervention is in itself so effective that many women will be satisfied with no treatment or with lifestyle modification alone. Rather than requesting a “lifetime commitment” to HRT from the outset, it is helpful to begin by making a short-term decision for HRT use, reassuring the patient that reassessments will be ongoing, and that every effort will be made to ensure that the regimen remains convenient, flexible and continues to lower her disease risks as new data emerge. Periodic testing of serum or saliva-free hormone levels (that which is unbound to sex steroid binding globulin, SSBG) can provide further reassurance regarding correct dosing of HRT. Urinary metabolites of bone reabsorption can also serve to reassure women at high risk for osteoporosis that bone balance is optimized with the chosen HRT regimen. Repeat bone density and lipid measurements at recommended intervals to confirm that desired goals of therapy are being met. A low threshold for follow-up office visits to review evolving concerns or symptoms is perceived as supportive and caring by patients.

Conclusion

The informed, aware woman whom many physicians treat today is no longer willing to comply with a therapeutic regimen that is good for “most women.” In appropriate patients we can hope they will remain on HRT long enough to attain its short-term symptom relief as well as long-term disease-prevention benefits. We must assess, for each individual woman, what she hopes to achieve with treatment, what adverse effects would be most difficult for her to tolerate, and what attributes of HRT are of greatest importance to her. We are then able to clearly explain why HRT may or may not be advisable for her as an individual and to collaborate in designing a treatment plan (medical, hormonal, nutritional, lifestyle/behavioral) that is most likely to meet her unique needs.
Ricki Pollycove, MD, MHS, FACOG, has practiced obstetrics and gynecology privately in San Francisco since 1981, with an increasing emphasis on menopause management. With a research background in the immunology of breast cancer, she continues to devote a significant portion of her practice to the special concerns of cancer survivors and women with multiple medical problems.

References:

Vassilopoulou-Sellin, Asmar, Hortobagyi, et al, Estrogen Replacement Therapy after localized breast cancer: Clinical outcome of 319 women followed prospectively, J Clin Oncol 17:1482-1487, 1999, Natrajan, Soumakis and Gambrell, Estrogen replacement therapy in women with previous breast cancer, Am J Obstet Gynecol 181: 288-295, 1999, Dew, Eden, Beller et al, A cohort study of HRT given to women previously treated for breast cancer, Climacteric 1:137-42, 1998,).