Estrogen replacement therapy (ERT) was primarily used to treat vasomotor symptoms, and it was increasingly viewed as a way to prevent chronic diseases of aging, including coronary heart disease (CHD) and cognitive impairment. (1-3) At least 40 percent of postmenopausal women in the United States were using ERT before the publication of the Women’s Health Initiative (WHI) report, (4) which addressed both the risks and benefits of ERT. (1) WHI trials addressed the most commonly used hormone formulations available at the time in the United States—mainly, conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA). Findings from these trials have been extensively published during the past decades. (5-7)

Manson et al. conducted an extensive study involving 27,347 postmenopausal women aged 50 to 79 years from 1993 to 1998 at 40 U.S. medical centers; 16,608 women with uterus present were randomized to oral CEE (0.625 mg/d) plus MPA (2.5 mg/d) (Prempro) or placebo, and 10,739 women with prior hysterectomy were randomized to oral CEE (0.625 mg/d) alone (Premarin) or placebo. CHD and invasive breast cancer served as primary outcomes. The study results were summarized in absolute terms as follows: For every 10,000 women taking CEE plus MPA per year, there were six more coronary events, nine more strokes, nine more pulmonary emboli, nine more cases of breast cancer compared to the placebo group. There were six fewer cases of colorectal cancer, one fewer case of endometrial cancer, six fewer hip fractures, and one fewer death compared to the placebo group. (1)

In young menopausal women (aged 50 to 54 years) with moderate or severe hot flashes and night sweats, administration of both the CEE and MPA and CEE alone caused substantial reductions in symptoms (64 percent and 28 percent, respectively, versus placebo at one year. ERT was also associated with statistically significant benefits for physical functioning, role physical, bodily pain, and general health. (1)

For context, almost half of women aged 60 to 65 years without hormone replacement therapy (HRT) report menopausal complaints and nearly two-thirds report sexual dysfunction. (8) Taken together with evidence that dyspareunia increases from early menopause to late menopause, it appears that vulvovaginal atrophy remains undertreated across all postmenopausal age groups. (8-9)

Most researchers have emphasized the importance of developing individual minimal effective dosing for each patient, with the goal of treating her symptoms and decreasing the risk of complications. Shufell et al. studied the risk of breast cancer in HRT users and concluded that a lower breast cancer risk extends to lower doses of ERT. (10)

To determine the relationship between hormone therapy use and BRCA1-associated breast cancer, Kotsopoulos et al. conducted a multicenter international cohort study. (11) They prospectively followed women with BRCA1 mutations who had undergone bilateral oophorectomy and had intact breasts. The authors followed 872 such patients for a mean of 7.6 years for every use of any type of ERT versus no use. The use of ERT compared with estrogen plus progesterone therapy reduced the subsequent risk of breast cancer (i.e., the 10-year actuarial risk of breast cancer was 12 percent versus 22 percent).

In 2008, we developed a computer algorithm (copyright RS 1800) to provide individual minimal effective dose for a patient based on the following parameters: age, weight, uterine status (i.e., present or absent), individual hormonal levels (estradiol, testosterone), and symptoms (i.e., minimal, moderate, or severe). (12) The following are examples of the algorithm’s application in individual cases:

• Patient 1

Age: 62 years

Weight: 78 kilograms

Uterus: present

Menopausal symptoms: severe

Hormone levels: within normal limits for menopause

Dose of Minivelle: 95 percent of patch

• Patient 2

Age: 42 years

Weight: 92 kilograms

Uterus: absent (ovaries also removed)

Menopausal symptoms: minimal (patient desires bone protection)

Hormonal levels: within normal limits for menopause

Dose of Minivelle: 64 percent of patch

We chose the indicated parameters because they appear to be most important in terms of treatment outcomes. The computer program was designed to develop the minimal effective dose of HRT to control patients’ symptoms. The computer algorithm is applicable to all forms of ERT, including but not limited to: pills, gels, sprays, injections, creams, and patches. The majority of our patients were using skin patches.**

Reassessment of dose is suggested every year, as many parameters (age, weight, severity of symptoms) are subject to change. Patient 3 is an example of such a case:

• Patient 3

Age: 56 years

Weight: 73 kilograms

Uterus: absent

Menopausal symptoms: severe

Hormonal levels: postmenopausal range

Dose of Minivelle: 87 percent of patch

• Patient 3 (10 years later)

Age: 66 years

Weight: 82 kilograms

Uterus: absent

Menopausal symptoms: minimal

Dose of Minivelle: 28 percent of path

In conclusion, we have developed and applied what appears to be the first attempt to use a computer algorithm for selecting a minimum useful dose of ERT based on parameters (weight, age, symptoms, etc.) and identifying treatment priorities for an individual patient. We hope that in the near future, patients will be able to input their personal data (for example, on a website) and receive a minimal individualized effective dose. The website’s recommendations will, under no circumstances, replace the patient’s clinicians. The final decision regarding the type and dose of ERT will rest with the patient’s healthcare provider. That said, we hope that this is a first step in more fully involving patients in their healthcare.

References & Notes

*Minivelle is a prescription brand of estradiol, used to treat symptoms caused by menopause or removal of the ovaries. It can also treat prostate and breast cancer, and prevent osteoporosis. Minivelle comes in 0.025, 0.0375, 0.05, 0.075, 0.1 preparations in patch form.

**Oral estrogens metabolize first in the liver, resulting in higher conversions of E2 to estrone, as opposed to transdermal estrogens that avoid first-pass metabolism, providing a lower and constant dose of estrogen stratified by dose, formulation, or route of delivery. (1)

1. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the women’s health initiative randomized trials. JAMA. 2013; 310(13): 1353-1368.
2. Anderson GL, Limacher M, Assaf AR, et al. Women’s Health Initiative Steering Committee. Effects of conjugation equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2004; 291(14): 1701-1712.
3. American College of Physicians. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med. 1992; 117(12): 1038-44.
4. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004; 291(1): 47-56.
5. Hays J, Ockene JK, Brunner RL, et al. Women’s Health Initiative Investigators. Effects of estrogen plus progestin in health-related quality of life. N Engl J Med 2003; 348(19): 1839-1854.
6. Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. WHI Investigators. Effects of estrogen plus progestin on stroke in postmenopausal women: the Women’s Health Initiative: a Randomized Trial. JAMA 2003; 289(20): 2673-2684.
7. Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. WHI Investigators. Effects of conjugated equine estrogen on stroke in the Women’s Health Initiative. Circulation. 2006; 113(20): 2425-2434.
8. Gartoulla P, Worsley R, Bell RJ, Davis SR. Moderate to severe vasomotor and sexual symptoms remain problematic for women aged 60 to 65 years. Menopause 2015; Jul;22(7):694-701.
9. Avis NE, Brockwell S, Randolph JF, et al. Longitudinal changes in sexual functioning as women transition through menopause: results from the Study of Women’s Health Across the Nation. Menopause 2009; 16: 442-452.
10. Shufelt C, Bairey Merz CN, Pettinger MB. Estrogen-alone therapy and invasive breast cancer incidence by dose, formulation, and route of delivery: finding from the WHI observational study. Menopause 2018; 25(9): 985-91.
11. Shilpa B, Grodstein F, Stampfer MJ, et al. Vaginal estrogen use and chronic disease risk in the Nurses’ Health Study. Menopause 2018; 12(17): 12-16.
12. Kaunitz AM. Should we rethink our use of vaginal estrogen? Medscape Apr 02, 2018.
13. Pinkerton JV, Kaunitz AM, Manson JE. Vaginal estrogen in the treatment of genitourinary syndrome of menopause and risk of endometrial cancer. Menopause 2017; 24(12): 1329-1332.
14. Petrikovsky BM. Hormone replacement therapy – computer assisted individual approach. W J Gynecol Women’s Health 2018; 1(4): 1-4.

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