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Obstetrics & Gynecology 2004;103:245-253
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Relief of Hot Flushes With New Plant-Derived 10-Component Synthetic Conjugated Estrogens

Wulf H. Utian, MD, PhD, Samuel A. Lederman, MD, Brenda M. Williams, MD, Rhonda Y. Vega, DVM, William D. Koltun, MD and Thomas W. Leonard, PhD

From The Cleveland Clinic, Rapid Medical Research, Cleveland, Ohio; Radiant Research, West Palm Beach, Florida; Boise, Idaho; Endeavor Pharmaceuticals, Inc, Wilmington, North Carolina; and Medical Center for Clinical Research, San Diego, California.

Address reprint requests to: Wulf H. Utian, MD, 5900 Landerbrook Drive, Suite 195, Mayfield Heights, OH 44124; e-mail: Utian{at}menopause.org.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
OBJECTIVE: A study was conducted to evaluate the safety and efficacy of 3 different doses of synthetic conjugated estrogens B, a new plant-derived 10-component conjugated estrogens product, for the treatment of menopausal vasomotor symptoms.

METHODS: This was a randomized, double-blind, placebo-controlled trial. Highly symptomatic menopausal women (N = 281) received 12 weeks of a once-daily oral treatment with 0.3 mg, 0.625 mg, or 1.25 mg of 10-component synthetic conjugated estrogen or placebo. Patients recorded the daily frequency and severity of hot flushes. Statistical analyses compared results at weeks 4, 8, and 12 with baseline values.

RESULTS: Statistically significant reductions (P < .05) in the frequency and severity of vasomotor symptoms were observed for all 3 dosage strengths of 10-component synthetic conjugated estrogen compared with placebo. The most commonly reported adverse events in all treatment groups were headaches. No difference in the incidence of treatment-related adverse events was seen between placebo and 10-component synthetic conjugated estrogen groups.

CONCLUSION: The 0.3-mg, 0.625-mg and 1.25-mg dose strengths of 10-component synthetic conjugated estrogen significantly reduced the frequency and severity of vasomotor symptoms compared with placebo, and were well tolerated during this 12-week study.

LEVEL OF EVIDENCE: I

Estrogen therapy (ET) is a widely used treatment for a range of symptoms associated with the reduction of endogenous estrogens that accompanies menopause. Distressing vasomotor symptoms, or "hot flushes," most often provoke menopausal women to initially seek relief through hormone therapy.1–3 Decades of clinical experience and use by millions of women have established ET as the standard treatment for relief of vasomotor symptoms. Recent events in hormone therapy research have led to a heightened interest in the use of low-dose ET options for vasomotor symptoms. A growing consensus within the medical community highlights the importance of low-dose therapy options and of tailoring ET to meet each individual patient’s requirements.4

Currently, the most commonly prescribed form of orally administered ET is a conjugated equine estrogen preparation (Premarin; Wyeth-Ayerst, St. Davids, PA) obtained from the urine of pregnant mares.5 For many years, this form of ET has been well accepted as an effective and generally safe treatment for relief of the vasomotor symptoms. Conjugated equine estrogen preparation from pregnant mares’ urine is composed of a mixture of 10 essential estrogens. This preparation also contains nonessential components and urinary substances in concentrations that vary from batch to batch.6 Recently, preparations containing conjugated estrogens derived from plant sources have been synthesized. To date, none of the preparations that have been synthesized contain all 10 essential estrogen components identified in conjugated equine estrogen, and specifically have lacked {Delta}8,9 dehydroestrone sulfate. This compound has been shown to have unique properties that may contribute to the overall beneficial biologic effects of conjugated equine estrogen.7–10

A new plant-derived 10-component synthetic conjugated estrogen, officially designated as synthetic conjugated estrogens B, contains all 10 essential estrogen components found in conjugated equine estrogen, including {Delta}8,9 dehydroestrone sulfate. All of the estrogenic components of 10-component synthetic conjugated estrogen and their relative concentrations are completely defined and contain no urinary impurities.

The study described in this article is the first multicenter, randomized, safety and efficacy study of 10-component synthetic conjugated estrogen (Enjuvia modified-release tablets; Endeavor Pharmaceuticals, Wilmington, NC) in women with moderate-to-severe vasomotor symptoms.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
A phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial in 4 parallel groups (0.3 mg, 0.625 mg, or 1.25 mg 10-component synthetic conjugated estrogen tablets, or placebo) was conducted in accordance with the ethical standards established by the Declaration of Helsinki of 1075 (revised in 1983). Before the onset of the trial, the study design and research parameters were reviewed and approved by the Food and Drug Administration, and each study center’s institutional review board approved the protocol.

The study population consisted of 281 postmenopausal women experiencing at least 7 moderate-to-severe hot flushes per day or 50 moderate-to-severe hot flushes per week. To be assigned to treatment, patients were required to be either surgically or naturally postmenopausal. Natural menopause was defined as amenorrhea for at least 12 months, or amenorrhea for 3 consecutive months with follicle-stimulating hormone levels greater than 40 mIU/mL and estradiol (E2) levels of less than 20 pg/mL. Patients must not have had any past or present conditions contraindicating estrogen or estrogen-progestin therapy. There were no study exclusions based on time elapsed since menopause, race, or body weight. A complete list of inclusion and exclusion criteria is presented in Table 1Go. Patients were required to discontinue any oral, topical, or parenteral depot estrogenic and progestogenic formulations, including "natural" remedies, at least 4 weeks before the study baseline visit.


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  		Table 1. Summary of Study Inclusion and Exclusion Criteria
 
When an eligible study patient was identified and had signed the informed patient consent form, the study site contacted the central randomization center and accessed an interactive voice response system. Through this system, patients were allocated to 1 of 4 treatment groups according to a computer-generated randomization scheme. Treatment numbers were assigned consecutively, in ascending order, beginning with the lowest available number. Patients were randomly assigned (1:1:1:1) to receive 0.3 mg, 0.625 mg, or 1.25 mg 10-component synthetic conjugated estrogen or placebo once daily for 12 weeks.

Patient drug supplies were packaged by an independent supply company according to the randomization scheme. The identity of the study medication was masked (ie, blinded). No patient, investigator, or other persons involved in the study knew the identity of the patient’s treatment. Because the 0.3-mg 10-component synthetic conjugated estrogen tablets are smaller than the 0.625-mg and 1.25-mg 10-component synthetic conjugated estrogen tablets, matching small (0.3-mg size) and matching large (0.625-mg and 1.25-mg size) placebo tablets were manufactured to mask tablet identity. Small active and placebo tablets and large active and placebo tablets were white and identical in outward appearance. Each patient self-administered 2 oral tablets (1 small and 1 large tablet) once daily. Nonhysterectomized patients also received a 14-day course of treatment with 10-mg/d medroxyprogesterone at the end of the study. This treatment was added as a safety measure to protect patients from risk of endometrial hyperplasia associated with unopposed estrogen exposure. No efficacy data were collected during the medroxyprogesterone course of treatment.

Treatment efficacy was assessed by measuring the change in the frequency and severity of vasomotor symptoms from baseline to weeks 4, 8, and 12 of the trial. Paper study diaries were given to each patient at the screening visit and at each of the study visits during the treatment period. Patients were instructed to record the occurrence of each hot flush in the study diary during the 2-week baseline period and during the 12-week treatment period. In the study diary, patients noted the occurrence of each hot flush and rated the severity as follows: 1 = mild (sensation of heat without perspiration), 2 = moderate (sensation of heat with perspiration but able to continue activity), or 3 = severe (sensation of heat with sweating causing the woman to stop activity). The study diary was bound with a page for each day and a space to record the date. Instructions on each page asked the patient, "Please specify whether you experienced mild, moderate or severe hot flushes" and "Please circle the corresponding code for the severity of each hot flush and circle AM or PM for each time."

Patients were examined and diaries were collected during a clinic visit every 4 weeks until the end of treatment. At the end of the 12-week treatment period, a subjective assessment of overall effectiveness of treatment was collected from each patient and investigator. Individuals were asked to rank the overall effectiveness of therapy in reducing symptoms as follows: 1 = excellent, 2 = good, 3 = fair, or 4 = poor.

Safety was monitored by collection of adverse events, clinical laboratory tests, vital signs, bleeding patterns, medical histories, and gynecologic, breast, and physical examinations. Patients were asked to rank and record the severity of adverse symptoms as follows: 1 = mild, 2 = moderate, or 3 = severe. The study site investigators made blinded determinations as to whether each adverse event was related to the study medication. During the course of treatment, nonhysterectomized patients also recorded the occurrence and severity of any uterine bleeding.

The sample size was calculated based on the planned analysis of covariance of the primary efficacy parameters, defined as the change from baseline at week 4 and at week 12. The significance level was defined at {alpha} = .05 and the power set at 80%. A common standard deviation of 6 was assumed, and the minimum difference, between treatment means, to be detected as significant was 3. A sample size of 64 patients in each treatment group was required. Based on an estimate of 10% nonevaluable patients, approximately 70 randomized patients per treatment group were planned to be included in the study.

The statistical model for the analysis of covariance included fixed-effect terms for center and treatment. Baseline value was used as a covariate in the analyses. Pairwise comparisons of treatment means (each active to placebo) were performed using the PDIFF option of the LSMEANS statement in SAS, 8.1 (SAS Institute, Cary, NC). Descriptive statistics and the Cochran-Mantel-Haenszel test for general association were used to make inference on assessment of overall effectiveness that was measured on a categorical scale.


   RESULTS
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
There were 281 patients randomized and assigned to treatment groups during the baseline visit. The "safety" analysis population was all randomized patients (N = 281). Efficacy analyses were performed by using the "intent-to-treat" population, which included all randomized patients who took at least 1 dose of study drug and had at least 1 complete day of pretreatment and post-treatment primary efficacy assessments (N = 276). A schematic of patient disposition is presented in Figure 1Go.



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  		Figure 1. Schematic of patient disposition. The intent-to-treat (ITT) population includes patients who took at least 1 dose of study drug and had at least 1 day of complete pretreatment and posttreatment assessments.

Utian. Hot Flushes and Synthetic Estrogens. Obstet Gynecol 2004.

 
Baseline characteristics of patients enrolled in the study are shown in Table 2Go. Patients ranged in age from 26 to 65 years, with a mean age of 51.1 years. No significant differences (P > .05) were detected between treatment groups in baseline characteristics of race, age, weight, or height (Table 2Go).


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  		Table 2. Summary of demographic and selected baseline characteristics–all enrolled patients
 
A total of 53 (19%) patients discontinued study participation during the 12 weeks of treatment. Discontinuation by treatment group was 19%, 15%, 17%, and 24% for the 0.3-mg, 0.625-mg, 1.25-mg 10-component synthetic conjugated estrogen groups and the placebo group, respectively. There was not a statistically significant difference between treatment groups in study discontinuation (P > .05; {chi}2 analysis). Overall, the most common reasons for discontinuations were protocol violations, adverse events, and loss to follow-up. These reasons were fairly evenly distributed across the active and placebo treatment groups.

Overall, patient compliance with the study drug regimen was high. Compliance for individual patients ranged from 85.7% to 100%. There was no statistically significant difference in mean compliance between the treatment groups during the 12-week treatment period (P > .05; analysis of variance model).

The mean number of moderate-to-severe hot flushes per week experienced during the 2-week period before study drug randomization ranged from a mean of 86.8 per week for patients in the 1.25-mg tablet treatment group to 104.3 per week for patients in the 0.3-mg tablet treatment group (Table 3Go). Clinically meaningful reductions in the number of moderate-to-severe hot flushes per week was observed for all doses of 10-component synthetic conjugated estrogen and at all analysis time points (weeks 4, 8, and 12). A decrease in frequency of moderate-to-severe hot flushes directly related to duration of treatment was seen for all dosage strengths (Figure 2Go, Table 3Go). By treatment week 12, patients in the 0.3-mg, 0.625-mg, and 1.25-mg groups experienced 72%, 85%, and 87% reductions from baseline in moderate-to-severe hot flushes, respectively, compared with a 47% reduction in the placebo group. These percent reductions in moderate-to-severe hot flushes were significantly different from placebo (P < .05) for all dosage strengths at 4, 8, and 12 weeks (Table 3Go).


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  		Table 3. Summary of Moderate-to-Severe Hot Flushes per Week: Intent-to-Treat Population
 


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  		Figure 2. Percent in the number of moderate-to-severe hot flushes. The percent change from baseline at weeks 4, 8, and 12 was significantly different from placebo (P < .05) for all 3 active treatment groups (based on analysis of covariance with baseline as a covariate, with effects for center and treatment).

Utian. Hot Flushes and Synthetic Estrogens. Obstet Gynecol 2004.

 
As is expected in studies of this type,11 a substantial placebo effect was observed, with a 34% reduction from baseline levels in the number of moderate-to-severe hot flushes at 4 weeks to a maximum of 47% reduction in frequency by the end of the study (Table 3Go). However, percent decreases in moderate-to-severe hot flushes were 55% or greater for all three 10-component synthetic conjugated estrogen doses at even the earliest assessment points.

Treatment with 10-component synthetic conjugated estrogen reduced the severity of vasomotor symptoms with duration of treatment at all doses (Figure 3Go). When severity was calculated with the formula (1 x mild) + (2 x moderate) + (3 x severe), a statistically greater reduction in severity compared with placebo was seen at all time points for patients in all 3 treatment groups (P < .05) (Figure 3Go).



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  		Figure 3. Severity of vasomotor symptoms in patients during the 12-week treatment period. Hot flush severity was defined as the sum of the number of mild, moderate, and severe hot flushes multiplied by severity (1 = mild, 2 = moderate, 3 = severe), as recorded by the patient during weeks 4, 8, and 12. The severity at weeks 4, 8, and 12 was significantly different from placebo (P < .05) for all 3 active treatment groups (based on analysis of covariance with baseline as a covariate, with effects for center and treatment).

Utian. Hot Flushes and Synthetic Estrogens. Obstet Gynecol 2004.

 
Figure 4Go provides a summary of the patients’ subjective assessments of the overall effectiveness of therapy after 12 weeks of treatment. Approximately 74%, 85%, and 90% of patients considered the overall effectiveness of 10-component synthetic conjugated estrogen good or excellent for reducing overall menopausal symptoms for the 0.3-mg, 0.625-mg, 1.25-mg tablets, respectively. All doses showed statistically better results (P < .05) than placebo, with only 48% of patients who received placebo rating their treatment as good or excellent. Investigator evaluations of overall effectiveness were similar to patients’ assessments.



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  		Figure 4. Patients’ assessment of overall (global) effectiveness of the study drug. Patients were asked, at the end of the 12-week study period, to evaluate the effectiveness of their treatment in relieving their symptoms as excellent, good, fair, or poor. * P < .001, active treatment versus placebo, for "good" plus "excellent" pairwise comparison.

Utian. Hot Flushes and Synthetic Estrogens. Obstet Gynecol 2004.

 
Ten-component synthetic conjugated estrogen was shown to be well tolerated and safe during the 12-week trial at all 3 dose strengths evaluated. The adverse events reported were consistent with those already known to be associated with estrogen treatment. Most adverse events (89%) were considered mild to moderate in intensity. A dose-related trend appeared in the percentage of patients reporting adverse events with overall incidences of 72%, 76%, 81%, and 71% for the 0.3-mg, 0.625-mg, and 1.25-mg 10-component synthetic conjugated estrogen groups and the placebo group, respectively (Table 4Go).


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  		Table 4. Adverse Events Summary: Safety Population
 
Overall, the most commonly reported adverse event in the active treatment and placebo groups was headache (Table 5Go). Including headaches, the 3 most commonly reported adverse events were pain and accidental injury in the 0.3-mg group, pain and abdominal pain in the 0.625-mg group, breast pain and nausea in the 1.25-mg group, and abdominal pain and nausea in the placebo group. It should be noted that there were no reports of breast pain by patients in the 0.3-mg 10-component synthetic conjugated estrogen group. The percentage of patients who discontinued the study because of adverse events was 5.7% for patients randomized to receive 10-component synthetic conjugated estrogen tablets and 8.3% for patients randomized to receive placebo (Table 4Go). Overall, there was no difference between the placebo and active-treatment arms in the number of treatment-related adverse events, with 35% of all patients receiving 10-component synthetic conjugated estrogen and 35% of the patients receiving placebo (Table 4Go) experiencing treatment-related adverse events.


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  		Table 5. Adverse Events Experienced by More Than 5% of Subjects: Safety Population
 
During the trial there were no reported cases of pulmonary emboli or venous thromboemboli. Five patients experienced serious adverse events during the trial. The serious adverse events reported were left ankle fracture (one 0.3-mg 10-component synthetic conjugated estrogen patient), exacerbation of chronic obstructive pulmonary disease (one 1.25-mg 10-component synthetic conjugated estrogen patient), right basal ganglion hemorrhagic stroke and high-grade stenosis of right internal carotid artery (one 0.625-mg 10-component synthetic conjugated estrogen patient), dehydration (one placebo patient), and cholecystitis (one 0.3-mg 10-component synthetic conjugated estrogen patient). The investigators, using their clinical judgment, made blinded assessments of causality and deemed that these serious adverse events were unrelated to the study drug.

Nonhysterectomized patients recorded any incidence and the severity of uterine bleeding or spotting during the trial. Overall, for patients in the 10-component synthetic conjugated estrogen treatment groups who experienced uterine bleeding, the average severity of bleeding was less than that for the patients taking placebo.


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
APPENDIX
 REFERENCES
 
In this study, plant-derived 10-component conjugated estrogens in modified-release tablets, officially designated as synthetic conjugated estrogens B, were evaluated for safety and effectiveness compared with a placebo tablet. Results showed that the 0.3-mg, 0.625-mg, and 1.25-mg tablets were significantly more efficacious than placebo in reducing the frequency and severity of hot flushes in a 12-week clinical trial. All 3 tablet strengths significantly reduced the frequency and severity of vasomotor symptoms within 4 weeks of initiating treatment. Percent reductions in moderate-to-severe hot flushes in this trial were significantly different from placebo at all timepoints, ranging from 55% for the 0.3-mg tablet after 4 weeks of treatment to 87% at 12 weeks of treatment with the 1.25-mg tablet.

A placebo effect of 34% to 47% reductions in the number of moderate-to-severe hot flushes from baseline was observed in this trial. This percentage is consistent with a mean 50% or greater reduction in hot-flush frequency observed in similar vasomotor trials.11,12 In 2001, MacLennan et al11 searched publication databases and requested data on controlled clinical trials conducted by pharmaceutical companies. They systematically reviewed data from double-blind, randomized, placebo-controlled vasomotor trials and found a mean reduction in vasomotor symptoms of 51%, from baseline to study completion, for subjects randomized to placebo in clinical trials of 3 to 6 months in duration.

Ten-component synthetic conjugated estrogen tablets contain the following 10 plant-derived synthetic conjugated estrogens: sodium estrone sulfate, sodium equilin sulfate, sodium 17{alpha}-dihydroequilin sulfate, sodium 17{alpha}-E2 sulfate, sodium {Delta}8,9-dehydroestrone sulfate, sodium 17ß-dihydroequilin sulfate, sodium 17ß-E2 sulfate, sodium equilenin sulfate, sodium 17{alpha}-dihydroequilenin sulfate, and sodium 17ß-dihydroequilenin sulfate. Cellulose-based polymers incorporated into the tablets allow for a consistent modified release, allowing the tablets to reach maximum plasma concentrations in the body at 8 to 9 hours after administration.13

We postulate that the efficacy of 10-component synthetic conjugated estrogen at the lowest dosage strengths may, in part, be attributed to the presence of {Delta}8,9 dehydroestrone sulfate. This compound has been shown to have unique estrogenic properties and high potency.7–9,14 In studies in which {Delta}8,9 dehydroestrone sulfate was administered alone, this compound was found to significantly reduce vasomotor symptoms.8

In summary, this clinical trial provided evidence that a range of 10-component synthetic conjugated estrogen dosages (0.3 mg, 0.625 mg, and 1.25 mg) effectively and significantly reduced the frequency and severity of vasomotor symptoms associated with menopause. All 3 tablet strengths were found to be well tolerated during the 12-week study period. The effectiveness of all 3 dose strengths of 10-component synthetic conjugated estrogen in reducing the frequency and severity of hot flushes in this clinical trial demonstrates that even tablet dosages as low as 0.3 mg/d will greatly improve symptoms for women experiencing frequent, intense hot flushes. This kind of symptom relief is important in that it may considerably improve a woman’s ability to function in daily life.1,15 The encouraging findings of this clinical trial demonstrate the effectiveness of a range of dosages in controlling moderate-to-severe hot flushes.


   APPENDIX
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
REFERENCES
 
GA 326 Study Principal Investigators (Other Than Article Authors)
Stephen C. Blank, Atlanta, GA; Lydia G. Corn, Sarasota, FL; Eugene M. Eisenman, Las Vegas, NV; Roger Ferland, Johnston, RI; Samuel W. Flannagan, Pittsburgh, PA; Sidney Funk, Atlanta, GA; Gita P. Gidwani, Cleveland, OH; Bryan R. Kurtz, Nashville, TN; Steven Landgarten, Tulsa, OK; John P. Lenihan Jr, Tacoma, WA; Thomas E. Melchione, Sacramento, CA; Paul Murphy, Fair Oaks, CA; Philip W. Ponder, Winston-Salem, NC; James P. Rice, Renton, WA; George H. Schade, Phoenix, AZ; Robert Sloves, Torrance, CA; Craig R. Sweet, Fort Myers, FL; Michael J. Troy, San Antonio, TX; Don Wheeler, Huntsville, AL.


   Footnotes
 
Financial Disclosure
This phase 3 clinical trial was conducted with the financial support of Endeavor Pharmaceuticals, Inc., Wilmington, NC. T.W. Leonard and R.Y. Vega are full-time employees of Endeavor Pharmaceuticals. Both employees hold options for common stock in Endeavor pursuant to the company’s stock option plan. Wulf Utian is a member of Endeavor’s Scientific Medical Advisory Board. Dr. Utian holds options for common stock in Endeavor issued pursuant to the company’s stock option plan.

doi: 10.1097/01.AOG.0000109428.87940.31

Received February 10, 2003. Received in revised form September 22, 2003. Accepted October 2, 2003.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
1. Barton D, Loprinzi C, Wahner-Roedler D. Hot flashes: aetiology and management. Drugs Aging 2001;18:597–606.[Medline]

2. Kaufert P, Boggs PP, Ettinger B, Woods NF, Utian WH. Women and menopause: beliefs, attitudes, and behaviors. The North American Menopause Society 1997 Menopause Survey. Menopause 1998;5:197–202.[Medline]

3. Utian WH, Shoupe D, Bachmann G, Pinkerton JV, Pickar JH. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril 2001;75:1065–79.[Medline]

4. Estrogen and progestogen use in peri- and postmenopausal women: September 2003 position statement of The North American Menopause Society. Menopause 2003;10: 497–506.[Medline]

5. Wysowski DK, Golden L, Burke L. Use of menopausal estrogens and medroxyprogesterone in the United States, 1982–1992. Obstet Gynecol 1995;85:6–10.[Abstract]

6. Leonard TW, Swarbrick J, Whittle RR, Hill EN, Ponder GW. Characterization of inactive components in conjugated equine estrogens. Scientific poster presented at: North American Menopause Society Annual Conference; October 5, 2002; Chicago, IL.

7. Baracat E, Haidar M, Lopez FJ, Pickar J, Dey M, Negro-Vilar A. Estrogen activity and novel tissue selectivity of delta 8, 9-dehydroestrone sulfate in postmenopausal women. J Clin Endocrinol Metab 1999;84:2020–7.[Abstract/Free Full Text]

8. Bhavnani BR, Cecutti A, Dey MS. Biologic effects of delta-8-estrone sulfate in postmenopausal women. J Soc Gynecol Investig 1998;5:156–60.[Medline]

9. Bhavnani BR, Cecutti A, Gerulath A. Pharmacokinetics and pharmacodynamics of a novel estrogen delta8-estrone in postmenopausal women and men. J Steroid Biochem Mol Biol 1998;67:119–31.[Medline]

10. Cenestin [package insert]. Cincinnati, OH: Duramed Pharmaceuticals, 2000.

11. MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review. Climacteric 2001;4:58–74.[Medline]

12. Stevens RE, Hanford K, Wason S, Cusack SL, Phelps KV. A 12-week clinical trial determining the efficacy of synthetic conjugated estrogens, A (SCE), in the treatment of vasomotor symptoms in menopausal women. Int J Fertil Womens Med 2000;45:264–72.[Medline]

13. Phase 1 study ENDV-01-002 results [data on file]. Wilmington, NC: Endeavor Pharmaceuticals. 2003.

14. Hammond CB. Therapeutic options for menopausal health: combating aging and disease [monograph]. Durham, NC: Duke University, 2000.

15. Sitruk-Ware R. Estrogen therapy during menopause: practical treatment recommendations. Drugs 1990;39:203–17.[Medline]




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