OESTROGEN (E2),  IVF  AND  OHSS

THE ROLE OF OESTROGEN IN FEMALE MENSTRUAL CYCLES

Oestrogen (E2), also known as oestradiol, is a hormone which plays a central role in the oocyte maturation process.  It also plays a secondary role in preparing the uterus for pregnancy.

This hormone is found in both the blood and in the follicular fluid. Levels of oestrogen vary throughout menstrual cycles, generally peaking at ovulation. Normal levels of oestrogen at ovulation are 500 to 1,000 pmol/L* in the blood. In order for healthy oocytes (follicles) to develop, their environment must be predominantly oestrogenic. Normally in each menstrual cycle, initially between 10 to 20 follicles start to develop with this number varying from person to person and declining with age. In most natural menstrual cycles, only one of the follicles (oocytes) survives and is released at ovulation. The cell death of the other follicles (oocytes) is a natural process known as atresia and is thought to be due to the presence of relatively high levels of androgens compared to oestrogen in the follicular fluid of the oocytes.

*pmol/L = pico (million millionth) mole/Litre

OESTROGEN AND IVF STIMULATION

In order to increase each patient’s chance of conception, IVF cycles aim to increase the number of eggs (oocytes) ovulated. Therefore, as part of the process of IVF, medications are used to stop or reduce the effect of atresia.  This leads to multiple follicle development and multiple oocytes ovulated.

IVF stimulation, therefore leads to raised oestrogen levels with blood levels in a typical IVF procedure from 5,000–15,000 pmol/L with the average about 9,000–10,000pmol/L. Although this is about ten times greater than in a normal menstrual cycle, the level in the follicular fluid around each oocyte remains the same. Consequently the follicles still all develop normally and the oocytes that are obtained fertilise and develop normally. However, more follicles are released at ovulation than in a normal menstrual cycle. For instance, the blood concentration of oestrogen may be ten times normal in an IVF cycle, but ten oocytes may be collected.

During an IVF cycle, the patient’s oestrogen levels are monitored by blood tests, and an assessment of when the optimum time to collect the oocytes is undertaken. It is typical to assess follicular maturation (the best time to collect the oocytes) not by the oestrogen value, but by the ratio of oestrogen in the blood to the number of follicles seen, to be more than 10mm in size on ultrasound scan at the time that ovulation is to be triggered.

OESTROGEN AND OVARIAN HYPERSTIMULATION SYNDROME (OHSS)

The higher oestrogen blood levels associated with IVF treatment are a possible (but not proven) cause of OHSS, which is one of the more serious complications of IVF since its inception in the late 1970s. Unfortunately, there is no known way of predicting accurately which patients may suffer this
complication or of preventing it from occurring. However, higher oestrogen levels have been linked to a higher risk of OHSS. Nationally the risk of OHSS is 2% per stimulated cycle with a third (0.6%) of these patients requiring hospitalisation to manage the condition. 

The link between oestrogen and OHSS is complicated by the fact that it does not just occur at a specific level of oestrogen. All that can be said is that the risk increases substantially over the range of 10,000 to 20,000pmol/L, but OHSS can occur at any level of Oestrogen and has been reported in non stimulated
natural cycles.

MEASURES TO REDUCE THE RISK OF OHSS

Most fertility centres will use as a cut off level of oestrogen of between 15,000 and 20,000pmol/L. If a patient’s Oestrogen reaches the cut off level oocyte collection is undertaken and all subsequent embryos produced are frozen. No embryos are replaced in that cycle because pregnancy is a known driver (but not a cause) of OHSS which can turn a mild case into a more severe case. Only in cases of very elevated oestrogen levels (greater than 30,000 pmol/L) would cancellation of the oocyte pickup be considered. Individual consultation with the specialist regarding high E2 levels, other requested blood levels and how the patient feels is considered when freezing all embryos.

Another measure to reduce the risk of OHSS that your doctor will consider is to change the trigger injection. hCG is most commonly used to trigger ovulation in stimulated IVF cycles and this may increase the risk of OHSS. Changing the trigger to a GnRH antagonist such as Lucrin has been shown to reduce the risk of OHSS.

Diagnosis of PCOS (Polycystic Ovarian Syndrome) is another risk factor taken into consideration by fertility clinics. If a patient has been diagnosed with this condition her doctor will be more conservative in the stimulation and management of treatment as OHSS is more likely to occur.

ADAPTED FROM INFORMATION PREPARED BY THE INFERTILITY FEDERATION OF AUSTRALASIA INC