Clinical:Case Study: Fine Tuning Hormone Replacement Therapy

Original materials created in December 1999 by Jan Werbinski, M.D., FACOG

History

CM is a 55 yo G2P2 married white woman whose last menstrual period was 5 years ago. Since then, she has reported symptoms of night sweats, hot flushes, decreased libido, and volatile moods. She has a history of poor dairy intake due to lactose intolerance. Her family history is negative for cancer, but her mother is recovering from a hip fracture at the age of 72, and her father died at age 55 of an MI. Her primary care physician started her on conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) cyclically about 4 years ago. While this regimen relieved her initial symptoms of night sweats, mood volatility, and decreased libido, CM noticed that whenever she takes the MPA, she begins having symptoms of depression, sluggishness, and irritability. She learned that if she skips the MPA part of the cycle, she can minimize her symptoms of estrogen withdrawal, and also completely avoid the adverse effects of the MPA. When CM complained of the adverse effects, her physician suggested that she decrease the number of withdrawal episodes with MPA to four per year, or every three months. The adverse effects of the MPA are so severe, however, that she would rather tolerate hot flushes and osteoporosis risk than take MPA. She asks if there is any other regimen available to control her symptoms, and offer her potential preventive benefits. Exam: CM has a normal physical exam, mammogram and pap smear. Data: FSH=74mIU; Estradiol <25 ng/dl; TSH=2.0(0.9-5.5); Total Chol=251(<200); HDL=44(>55); LDL=174(<160); C/HDL ratio 5.7. Her DEXA scan shows a T score at the hip of -2.7 (osteoporosis).

Discussion

Scientists have known for decades that the symptoms of menopause signal a decrease in estrogen levels in a woman’s body. Before estrogen was first synthesized in 1920, alchemists and herbalists controlled many symptoms of the climacteric with herbs, including red clover, soy, and black cohosh. In 1975, when Smith and Ziel published their classic studies showing an increased risk (8-13%) of uterine cancer in women on estrogen, consideration was given to new regimens to reduce such a risk. Gambrell, in 1983, showed that addition of medroxyprogesterone acetate would almost eliminate higher risk of uterine cancer associated with estrogen use alone.In Gambrell’s original studies, approximately 18% of women complained of depression during the MPA component of their therapy. We now know that significant numbers of women will experience adverse effects on MPA, including depression, bloating, fluid retention, headaches, mood swings, dysfunctional bleeding, breast tenderness, and irritability. Cramping, pain, and hot flushes are not usual side effects. Occasionally, a more severe clinical depression will require antidepressant therapy or even hospitalization. Other recent concerns raised about progestins surround their potential to block some beneficial effects of estrogen on the body. Among these concerns are counteracting the positive effects estrogen has on HDL levels, and coronary vasodilation. Several progesterone regimens have been evaluated and tested in attempts to prevent endometrial cancer, but also minimize potential adverse effects. The PEPI (Postmenopausal Estrogen-Progestin Intervention) Trial confirmed that regimens using daily doses of 2.5 mg MPA are as effective at preventing hyperplasia as those using 13 days of 10 mg MPA.5 PEPI also showed effective prevention of hyperplasia when 12 days of another compound, micronized progesterone, is used. In fact, the regimen utilizing micronized progesterone not only prevented hyperplasia due to estrogen, but also improved the lipid profile to a greater degree than the regimen utilizing MPA. This study has led to the Federal Drug Administration (FDA) approval of micronized progesterone for hormone replacement therapy.

Micronized progesterone is available by prescription in Europe and Canada, and now in the US as an FDA approved pharmaceutical. Compounding pharmacies can also prepare micronized progesterone and estrogens in emollient creams for patients who prefer that method of administration. The creams are similar to FDA approved transdermal patches, and may be as effective at elevating serum hormone levels. The data are unclear as to whether creams maintain bone density and favorable lipid parameters. Micronized progesterone has been studied for many years to evaluate claims that it is effective in controlling the mood disorder associated with premenstrual syndrome (PMS). Results have been conflicting, but a few studies have shown it to be effective.6 While the data regarding treatment of PMS is conflicting, none of the studies have shown an association of micronized progesterone with dysphoria or irritable mood.

Plan

A Women’s Health physician was consulted who recommended continuing the hormone replacement therapy for both acute symptoms of menopause, and for long term preventive considerations, but substituted oral micronized progesterone at 200 mg once daily for 12 days each cycle, rather than MPA. CM’s “depressive symptoms, irritability, and sluggishness” resolved completely on this regimen. She began having light, controlled three-day periods of withdrawal bleeding after her micronized progesterone cycle was completed. While many women view periods as a deterrant to using certain regimens of HRT, CM viewed light menstrual bleeding as a small inconvenience compared to her understanding of symptom benefit and potential long term prevention. This underscores the need for informed patient involvement in choice to use HRT, and individualized regimens.

A plethora of studies now demonstrate effectiveness and low adverse effect profiles of various HRT regimens. As physicians who care for women, we have an imperative to stay current with the data to create individualized options for our patients. In this way we can facilitate adherence to chosen and beneficial treatment plans.

References

1. Smith DC, Prentice R, et al. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med, 1975;293:1164-1167

2. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med,1975;293:1167-1170.

3. Gambrell, RD Jr, Bagnell CA, Greenblatt RB: Role of estrogens and progesterone in the etiology and prevention of endometrial cancer: review. Am. J. Obstet. Gynecol,1983;146:696-707

4. Personal Communication. K.Johnson, MD

5. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. JAMA, 1996;275:370-375

6. Dennerstein L., et al. Progesterone and the premenstrual syndrome: a double blind crossover trial. BMJ, 1985;290:1617-1621

For your patients

Perimenopause: Preparing for Change by Nancy Teaff, MD. Second Revised Edition. Prima Publishing:1999.

Screaming to be Heard by Elizabeth Lee Vliet, MD. M. Evans, and Co., Inc., NewYork:1995 Dr. Susan Love’s Hormone Book: Making Informed Choices About Menopause by Susan M. Love, MD, with Karen Lindsey. Random House Inc., New York: 1998