The acute toxicity of estriol in animals is very low. Symptoms that may occur in the case of an acute oral overdosage are nausea, vomiting and possibly withdrawal bleeding in females. No specific antidote is known. If necessary a symptomatic treatment should be instituted.
None stated.
The following adverse reactions, associated with estrogen treatment may occur during estriol therapy or overdose: Nausea and vomiting, breast tenderness or pain in the breasts, vaginal bleeding or spotting during or on withdrawal of therapy, excessive production of cervical mucus, headache.
From Literature and safety surveillance monitoring, the following adverse reactions have been reported:
| System organ class | Adverse reactions* |
| General disorders and administration site conditions | Application site irritation and pruritus Influenza-like illness |
| Reproductive system and breast disorders | Breast discomfort and pain |
*MedDRA version 9.1
These adverse reactions are usually transient, but may also be indicative of too high a dosage.
Breast cancer risk
- An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen therapy for more than 5 years.
- Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestagen combinations.
- The level of risk is dependent on the duration of use.
- Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.
Million Women study- Estimated additional risk of breast cancer after 5 years' use
| Age range (yrs) | Additional cases per 1000 never-users of HRT over a 5 year period* | Risk ratio# | Additional cases per 1000 HRT users over 5 years (95%CI) |
| Estrogen only HRT | |||
| 50-65 | 9-12 | 1.2 | 1-2 (0-3) |
| Combined estrogen-progestagen | |||
| 50-65 | 9-12 | 1.7 | 6 (5-7) |
| #Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use * Taken from baseline incidence rates in developed countries. | |||
US WHI studies - additional risk of breast cancer after 5 years' use
| Age range (yrs) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio & 95%CI | Additional cases per 1000 HRT users over 5 years (95%CI) |
| CEE estrogen-only | |||
| 50-79 | 21 | 0.8 (0.7 - 1.0) | -4 (-6 - 0)* |
| CEE+MPA estrogen & progestagen‡ | |||
| 50-79 | 14 | .2 (1.0 - 1.5) | +4 (0 - 9) |
‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users. * WHI study in women with no uterus, which did not show an increase in risk of breast cancer
Ovarian cancer
Long-term use of estrogen-only and combined estrogen-progestagen HRT has been associated with a slightly increased risk of ovarian cancer. In the Million Women Study 5 years of HRT resulted in 1 extra case per 2500 users.
Risk of venous thromboembolism
HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HT. Results of the WHI studies are presented:
WHI Studies - Additional risk of VTE over 5 years' use
| Age range (yrs) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio & 95%CI | Additional cases per 1000 HRT users |
| Oral estrogen-only | |||
| 50-59 | 7 | 1.2 (0.6 - 2.4) | 1 (-3 - 10) |
| Oral combined estrogen-progestagen | |||
| 50-59 | 4 | 2.3 (1.2 - 4.3) | 5 (1 - 13 |
* Study in women with no uterus
Risk of coronary artery disease
The risk of coronary artery disease is slightly increased in users of combined estrogen-progestagen HRT over the age of 60.
Risk of ischaemic stroke
The use of estrogen-only and estrogen-progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke.
WHI studies combined - Additional risk of ischaemic stroke* over 5 years' use
| Age range (years) | Incidence per 1000 women in placebo arm over 5 years | Risk ratio and 95%CI | Additional cases per 1000 HRT users over 5 years |
| 50-59 | 8 | 1.3 (1.1- 1.6) | 3 (1-5) |
*no differentiation was made between ischaemic and haemorrhagic stroke.
Other adverse reactions have been reported in association with estrogen-only and estrogen/progestagen combined treatment:
- Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer.
- Gall bladder disease.
- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.
- Probable dementia over the age of 65.
No particulars
Estriol: The active ingredient, synthetic estriol, is chemically and biologically identical to human estriol. It substitutes for the loss of estrogen production in menopausal women, and alleviates atrophic vaginitis.
Ovestin Cream contains the synthetic hormone estriol. In the years just before and after the menopause (whether naturally or surgically induced) estriol can be used in the treatment of urogenital symptoms and complaints related to estrogen deficiency. In cases of vaginal atrophy estriol induces normalisation of the vaginal epithelium and thus helps to restore the normal microflora and a physiological pH in the vagina. As a result it increases the resistance of the vaginal epithelial cells to infection and inflammation.
Estriol is relatively short-acting estrogen due to its short nuclear retention time in endometrial cells, its low affinity for plasma proteins and partly as a result of this, its rapid metabolic clearance. Endometrial proliferation is not expected when estriol is given in a single daily dose, since this requires sustained, occupancy of the nuclear estrogen receptor. As a consequence, undesired vaginal bleeding rarely occurs during treatment with estriol and an increased risk of endometrial carcinoma is unlikely.
Relief of urogenital symptoms was achieved during the first weeks of treatment.
After administration of Ovestin Cream, estriol is also absorbed from the vagina into the general circulation, shown by a sharp rise in plasma estriol, followed by a gradual decline.
After 3 weeks of administration of a single daily dose, a similar absorption pattern to that seen for a single application was observed.
Daily treatment with 0.5 mg of estriol (in 0.5 g of cream) leads to a sharp rise in unconjugated plasma estriol levels to 110 pg/ml at one hour from previously undetectable levels (<12 pg/ml). This was followed by a gradual decline during the next 5 hours to around 60 pg/ml.
On day 21 of treatment, mean baseline estriol levels of about 26 pg/ml rose to a mean peak value of 95 pg/ml at 1 hour. A decline similar to that seen on day 1 was observed during the next 5 hours.
Vaginal administration permits the absorption of the active (unconjugated, or free) form of estriol into the blood for transport to the target tissues, prior to its inactivation via conjugation by enterohepatic enzymes.
As far as is known Ovestin has no effect on alertness and concentration.
