Is Intravaginal Estrogen Safer Than Oral Estrogen?

Subject: Nursing
Pages: 5
Words: 1278
Reading time:
5 min
Study level: College

Postmenopausal women suffer from a lot of problems due to a chronic lack of estrogen. The common problems associated with menopause are vasomotor instability, vaginal dryness and atrophy, urinary tract infections and other urinary symptoms like increased frequency, urgency and incontinence, osteoporosis, etc (Schaffer, 1996). Around 45% of postmenopausal women may complain of symptoms related to vaginal atrophy. It is generally found that 10-15% of the women suffer from vaginal dryness within a year after menopause whereas 40-45% complain of the same problem with five years of menopause. Therefore, a lot of postmenopausal women are put on hormone replacement therapy (HRT) to overcome one or more of these above-mentioned symptoms. These symptoms affect the quality of life of postmenopausal women to a greater extent. They not only reduce their daily activities but also lead to social isolation and depression (G, 1993).

HRT is quite effective in relieving postmenopausal symptoms. A meta-analysis of 10 trials shows that HRT resulted in significant improvement in all the outcome measures (Cardozo, 1998). It further showed that vaginal estrogen provides more symptomatic relief compared to other routes of administration. But it was identified that only a few studies provided results beyond 6 months of HRT use.

Although HRT has been used for a long time now, there are many concerns regarding its safety. This is because estrogen hormone replacement has been associated with vaginal bleeding, exacerbation of migraines, increased risk of breast and uterine cancer, coronary artery disease and thrombosis (Investigators, 2002). Thus it is contraindicated in people with CAD, recent venous thrombosis, liver disease and unexplained vaginal bleeding. Due to all these risks associated with estrogen hormone replacement therapy, various forms and types of hormone replacement therapies have been tried to overcome these problems. Several forms of HRT are available for systemic (oral, injectable, transdermal and nasal) and local use (vaginal rings, vaginal creams and slow-releasing tablets).

Nowadays, Estriol (a less potent estrogen) is used in HRT as it reduces menopausal symptoms and is much safer than more potent estrogens as it does not increase the risk of endometrial and breast cancer (Takahashi, 2000) (Melamed, 1997) (Weiderpass, 1999). Other forms of estrogen apart from oral estrogens like transdermal patches and intravaginal creams, gels and rings have been used to reduce the side effects and risks associated with HRT.

Nowadays, it is commonly believed that intravaginal estrogen is safer as compared to oral estrogen but there is scarce evidence to support this belief (Cameron, 2003). A low dose of intravaginal estrogen is required as it bypasses first-pass metabolism. Therefore, it can be postulated that it will have lesser systemic side effects but the main concern is that continuous exposure can lead to endometrial hyperplasia. A recent review showed that seven clinical and epidemiological studies revealed no significant increase in the risk of endometrial hyperplasia or cancer associated with the use of intravaginal estrogen (Cameron, 2003). Only a few studies in the review reported endometrial hyperplasia but in those studies, higher doses of intravaginal estrogen were used. It was further concluded in the review that estrogen tablets and low-dose estrogen rings are the safest HRT as reported by the clinical trials conducted so far.

The Cochrane review compared different intravaginal forms of estrogen HRT (Suckling, 2003). This review concluded that all of the forms (creams, tablets, rings, etc) are effective in relieving vaginal atrophy symptoms but vaginal rings and tablets pose a lesser risk of developing endometrial hyperplasia and cancer compared to intravaginal cream. Intravaginal rings and tablets even showed lesser side effects in all the trials compared to intravaginal estrogen creams.

Several trials have been done to determine the safety of these various forms of HRT but a conclusive decision has not been reached yet. Therefore, it is important to determine which form of estrogen replacement is safer to overcome postmenopausal symptoms in women as postmenopausal symptoms are very common and can be very disturbing and disabling for a lot of women.

The purpose of this study is to compare the effects of oral and intravaginal estrogen to preserve vaginal integrity and treat vaginal dryness and atrophy. This study also intends to compare the safety of long-term use of oral and intravaginal estrogen.


This will be a single-center study conducted at Central Hospital, Detroit. It will be a single-blinded, prospective, randomized controlled trial. All ethical issues will be considered and approval from the research ethics committee will be taken. The purpose of the research and all the procedures will be explained to the study participants and written informed consent will be obtained.

All the postmenopausal women with vaginal dryness and atrophy requiring HRT during the study period will be included in the study. Patients in whom HRT is contraindicated will not be included in the study as this can be a major confounding factor in the study results.

Randomization will be done with the help of precoded numbers sealed in envelopes which will be opened by the research nurse at the time of treatment allocation to the patients. Participants will be randomly divided into two groups: Group 1- intravaginal estrogen and Group 2- oral estrogen. Treatment will be initiated on the initial visit of the patients after proper assessment. The consultant assessing the patients will be blinded and will not be aware of the treatment group of the patients. After the initial assessment, the patients will be assessed at regular intervals: 1 month, 3 months, 6 months, and 1 year.

Several subjective and objective outcome measures will be used to assess the benefit and adverse effects of estrogen in patients in both groups. Subjective assessment will include the symptoms of the patient (vaginal dryness, itching, dyspareunia, etc) and the clinical appearance of a vaginal surface (pale, dry, fragile, etc). Objective assessment will include vaginal pH and cytology. The safety of the treatment will be assessed by the appearance of systemic or local adverse effects, endometrial thickness, endometrial biopsy, progesterone challenge test, and breast tenderness.

A standard protocol will be followed to assess all the patients to minimize errors and variability of results. Before the start of the study, a two-day workshop will be conducted to orient all the researchers to the study protocol and methodology.

At the end of the study, data will be organized properly and data analysis will be done using SPSS (version 16.0). All the outcome measures in the two groups will be compared to conclude whether intravaginal estrogen is safer compared to oral estrogen or not. A chi-squared test will be used to compare categorical variables and a student t-test will be used to compare continuous variables.

Ethical Considerations

All patients will be well informed about the risks and benefits of participation in the study. Written informed consent will be taken from the participants and they will have the right to withdraw from the study at any time. All the information obtained from the participants will remain confidential and anonymity will be maintained at all times.


The weakness of this study is that it is a single-center study and therefore, may not reflect the true safety picture of the use of intravaginal estrogen. Since it is a single-blinded study, it would have been more stronger and reliable if it would have been double-blinded. There can be individual variations in the assessment by different consultants. This will introduce a bias in the study results.


The results of this study will have wider applications as it will provide a long-term follow-up of patients using intravaginal estrogen. There is a dire need for such studies to establish the safety profile of estrogen hormone replacement therapy as only a few studies provide results of long-term use of intravaginal estrogen HRT.


  1. Cameron. (2003). Best practice with vaginal (unopposed) oestrogens. Trends in Urology, Gynaecology & Sexual Health , 8.
  2. Cardozo. (1998). Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women. Obstet Gynecol , 92, 722-7.
  3. G, D.-T. (1993). The psychological status of female with urinary incontinence. Zentralblatt , 115, 332-335.
  4. Investigators, W. G. (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA , 288, 321-333.
  5. Melamed. (1997). Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol. Mol Endocrinol , 11(12), 1868-78.
  6. Schaffer. (1996). Urogenital effects of the menopause. Baillieres. Baillieres Clin Obstet Gynaecol , 10, 401-417.
  7. Suckling. (2003). Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev , 4.
  8. Takahashi. (2000). Safety and efficacy of oestriol for symptoms of natural or surgically induced menopause. Hum Reprod , 1028-36.
  9. Weiderpass. (1999). Low-potency oestrogen and risk of endometrial cancer: a case-control study. Lancet , 353(9167), 1824-8.