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Warner Study

Use of Oral or Subcutaneous (pellet) Estradiol 17B with Natural Progesterone in 200 Patients Followed for 10 years

Philip Warner, MD
201 "D" Street, Suite K
Marysville, CA 95901
Tel: 530-749-8511


Two hundred patients from a private practice of OB/GYN were started on hormonal replacement therapy for a variety of symptoms.

The patients presented with symptoms relating to ovarian hormone imbalance or hormone deficiency and were all seen initially by the author. Many of the patients were seen in consultation for hormonal problems after having an evaluation elsewhere. The patients were seen at +1,3,6 month intervals and then annual visits thereafter. At each visit, the women were interviewed and questionnaires about symptoms or bleeding patterns were completed. They had a complete physical examination and initial blood work including FSH1 Blood Panel, Cholesterol, HDL and LDL. Mammograms were obtained according to ACOG recommendations. Endometrial biopsies, pelvic sonography, D&C, and hysteroscopy were accomplished as clinically indicated.

The patients were divided into two groups:

  1. Perimenopause (PEM) defined by irregular or excessive menstruation or clinical symptoms and FSH> 15 IU/L.
  2. Postmenopause (POM) defined by natural or surgical absence of menses. There were 73 (PEM) patients and 127 (POM) patients. Many of the (PEM) patients might also be defined as having premenstrual syndrome. The initial complaints of the (PEM) patients included dysfunctional uterine bleeding, cyclic vascular headaches, anxiety, depression, insomnia, diminished libido, breast tenderness, bloating and dysmenorrhea. The (POM) patient’s symptoms included hot flashes, night sweats, vaginal dryness, dysuria, dysparuenia, diminished libido, depression, memory loss and insomnia.

The patients in Group 1 (PEM) received sequential estradiol [E2] and progesterone [P] therapy, while Group 2 (POM) received combined E2 & P therapy. A subgroup of (POM) patients who did not respond to oral therapy satisfactorily were placed on subcutaneous (pellet) implants. Of these patients, those with an intact uterus received oral micronized progesterone daily, while those with surgical menopause and no uterus received only the estradiol implants. In some cases, estradiol and testosterone implants were utilized.

The hormones in Group 1 (PEM) patients were micronized estradiol 17B USP 0.5 mgm mixed with alpha lactose in gelatin capsules (Bajamar Labs, St. Louis, MO) taken 25 days a month with micronized USP progesterone 100 mgm in gelatin capsules (Bajamar Labs, St. Louis, MO) taken BID, 14 days per month.

The hormones in Group 2 (POM) patients were micronized estradiol 17B 0.35 mgm and micronized progesterone 100 mgm both in a single capsule taken daily. In some cases the dose was increased to one capsule BID. The implants were 25 mgm estradiol pellets, average 2 pellets and 75 mgm testosterone proprionate pellet. (College Pharmacy, Colorado Springs, CO.)

Table 1 Hormone Replacement Therapy: (PEM) Patients
E2 25 days/month P 14 days/month N=73

Symptom Initial Visit 1mo. 6mo. 12mo. Current
Dysfunctional Uterine Bleeding 58 35 12 3 10
Cyclic Vascular Headaches 15 15 8 2 2
Anxiety 43 40 22 18 15
Depression 26 9 12 11 6
Breast Tenderness 42 38 6 0 0
Bloating 19 18 3 0 0
Dysmenorrhea 32 21 11 10 9

Table 2 Hormone Replacement Therapy: (POM) Patients
E2 & P combined in One Capsule Daily* N=127

Symptom Initial Visit 1mo. 6mo. 12mo. Current
Hot Flashes 110 85 22 3 0
Vaginal Dryness 56 50 37 10 0
Dysuria 22 10 0 0 0
Diminished Libido 62 62 48 35 25
Depression 83 76 52 38 18
Memory Loss 96 90 73 45 38
Easy Crying 115 102 65 25 22
Insomnia 112 96 15 0 0
Uterine Bleeding or Spotting 35 32 0 0 0

Thirty-two of the original two hundred patients are no longer being seen due to death, moving away from the area, or dissatisfaction with treatment. The remaining patients are continuing follow-up visits. The group 1 (PEM) patients who initially showed dysfunctional uterine bleeding patterns reverted to normal patterns in 75% of the cases. However, this is modified by the fact that some of the persistent cases subsequently underwent hysterectomy or endometrial ablation. Additionally, at an average age of 50, the (PEM) patients were successfully convened to (POM) patients by switching to a combined E2 & P regimen. It generally took 6 months after switching regimens for the amenorrheic pattern to occur.

In Table I the number of patients with residual symptoms at varying intervals of time are listed. Within one year, these patients showed regulation of their menstrual pattern and significant decrease in the symptoms associated with premenstrual syndrome. Those patient% continuing with significant hyper or polymenorrhea eventually came to hysterectomy or endometrial ablation. The menstrual flow pattern decreased the longer the patient was on sequential hormone therapy. When the patients were switched to a combined regimen, they eventually became amenorrheic. In some cases the decision to switch therapy was dictated by failure of withdrawal bleeding after 1 to 2 months of progesterone only therapy. This can be an indicator to convert a (PEM) patient to a (PONI) patient instead of an arbitrary age of 50.

In table 2, the (POM) patients showed excellent relief of hypoestrogenic symptoms on the combined regimen. In addition, compliance was aided by the necessity of taking only one capsule per day containing both E2 & P. The patients were especially satisfied by having no sporadic bleeding or spotting while obtaining benefits of estrogen therapy. Forty-two patients continued to complain of some hypoestrogenic symptoms and were given estradiol (and in some cases testosterone) pellets. This mode of treatment is very effective in this select group of patients. The use of hormone implants was initiated by Dr. Robert Greenblatt in the 1930s. It provides a constant hormone release and stable blood level for the patient who otherwise is unable to achieve relief of symptoms by the oral or transdermal (patch) route.

The perimenopausal patient with her associated symptoms of abnormal bleeding patterns, premenstrual syndrome, and vascular headaches can benefit from hormone balance therapy. The use of sequential estradiol 17B with oral micronized progesterone offers an excellent method of therapy. It does not appear advantageous to substitute progestogens which while effective can "muddy the water" by aggravating symptoms of breast tenderness, depression, bloating etc. - the very symptoms we are trying to relieve.

The postmenopausal patient benefits from combined estradiol and micronized progesterone therapy without the continued bleeding pattern associated with the use of medroxyprogesterone. The progesterone also does not alter the favorable changes in lipoproteins induced by estrogen. In addition, compliance is aided by the two hormones together in one capsule being ingested once per day.

It remains to be proven if the protection in the long term against osteoporosis and cardiovascular disease will remain the same with these agents. However, low dose micronized 17B estradiol has been shown to prevent bone loss in postmenopause women and micronized oral progesterone has been shown to be active in bone metabolism altering bone turnover and acting directly on the osteoblast to promote bone formation.

Finally, alternative routes of therapy must be utilized in individual patients for whom oral therapy is not successful. Subcutaneous (pellet) implants are an effective, simple method to be utilized when necessary.

Please refer any inquires to:

Phillip 0. Warner, M.D.
Menopause Institute of Northern California
700 W. Parr Ave., Suite D
Los Gatos, CA 95030


  1. World Health Communications Inc. News Letter: May, 1992.
  2. Henderson, 13.E., Paganini-Hill, A., and Ross, R.K.: Estrogen replacement therapy and protection from acute myocardial infarction, Am. J. Obstet. Gynecol. 159:312-7, 1988
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  10. Hargrove, J.T+, Maxson, W.S., Wentz, A.L., and Burnett, L.S.: Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone, Obstet. Gynecol. 73:606-12, 1989.
  11. Chakmakjian, L., et a!.: Bioavailability of progesterone with different modes of administration, J. of Reprod. Med. 32:443-447, 1987.
  12. Brincat, M., Magos, A., Studd, J.W.W., et al.: Subcutaneous hormone implants for the control of climacteric symptoms, Lancet 1:16, 1989.
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  14. Ettinger, B., Genant, H.K., et al.: Low dosage micronized 17B estradiol prevents bone loss in postmenopausal women, Am. J. Obstet. Gynecol. 166:479-88, 1992.
  15. Prior, J.D.: Progesterone as a bone-trophic hormone, Endocr. Rev. 11:386, 1990.






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Updated  05/16/2010