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Gonadotropins control the ovarian cycle
In the female body, the ovarian cycle is controlled by two hormones called gonadotropins: follicle-stimulating hormone (FSH) and luteinising hormone (LH). These two hormones are produced by a small gland located in the brain: the pituitary gland. Their release into the bloodstream is induced by a neurohormone called GnRH. This is produced by the hypothalamus, also located in the brain.
FSH and LH then act directly on the functioning of the ovary
FSH stimulates the maturation of ovarian follicles during the follicular phase. The growing follicles then secrete oestrogens which act on the endometrium and the pituitary gland. In the endometrium, oestrogens stimulate cell proliferation and thus encourage the progressive thickening of the uterine mucosa, which is essential if the embryo is to implant. In the pituitary gland, oestrogens cause an increase in the release of LH.
Oestrogens are therefore responsible for an "LH peak" which is specific to ovulation. This increase in LH production induces rupture of the ovarian follicle, which then releases its oocyte into the Fallopian tube. Following ovulation, LH is responsible for transforming the follicle into a corpus luteum, which produces progesterone. Under the effect of progesterone, the endometrium becomes receptive to the embryo.
What is an ovarian stimulation?
The aim of ovarian stimulation is to optimise the follicular phase of the ovarian cycle. Hormonal treatment is prescribed: the doses are adapted to the patient's clinical data, in particular the ovarian reserve. This treatment consists of a daily subcutaneous injection of hormones. It is up to the patient to administer the treatment herself! Ovarian stimulation is offered to :
Ovarian stimulation as part of a fertility treatment plan
During a fertility treatment, the hormonal treatment period is divided into three stages: blocking the ovaries, ovarian stimulation and ovulation induction.
BLOCKING THE OVARIES
In order to be able to fully control the patient's ovarian and menstrual cycles, she undergoes a phase of blocking the ovaries by inhibiting hormone production by the pituitary gland (FSH and LH). This is achieved by means of two classes of medication :
An ultrasound scan and blood test are carried out 15 to 20 days after the start of treatment to ensure that the ovaries are at rest. The second phase of hormone treatment can then begin: ovarian stimulation.
OVARIAN STIMULATION
As part of an intrauterine artificial insemination protocol, ovarian stimulation is used to improve ovulation and control its timing. Hormonal treatment induces the maturation of a maximum of three ovarian follicles. The aim is to reduce the risk of twin pregnancies. In vitro fertilisation protocols (conventional IVF or IVF-ICSI), on the other hand, aim to stimulate the ovaries as much as possible so that they produce as many oocytes as possible. The treatment used consists of injecting gonadotropins (Gonal F® or Puregon®) which mimic the action of FSH: these stimulate the ovaries and act on the growth and maturation of the follicles.
INDUCING OVULATION
When the ovarian follicles have reached a satisfactory number and size, ovulation is triggered. To do this, a single injection of gonadotropic chorionic hormone (Ovitrelle®) is given to mimic the LH peak specific to ovulation. Ovulation occurs approximately 30 hours after the injection.
In the case of conventional IVF or IVF-ICSI: oocyte puncture will take place before ovulation, i.e. before the ovary releases the oocytes into the fallopian tubes. However, triggering ovulation is necessary to induce oocyte maturation: only mature oocytes can be fertilised by a sperm cell.
In the case of intrauterine insemination: during artificial insemination, ovulation takes place in the usual way: the oocytes are released into the fallopian tubes where fertilisation by a spermatozoon takes place.
The timing of ovulation induction is very important: the oocyte retrieval (in IVF) or sperm transfer (in intrauterine insemination) is planned by the medical team 36 hours after the induction.
Simple ovarian stimulation
Simple ovarian stimulation is a much lighter process than that used for patients undergoing fertility treatment. In this context, ovarian stimulation encourages the maturation of ovarian follicles in women who ovulate poorly or not at all. The aim is to enable the ovary to produce a maximum of one or two follicles (containing oocytes), in order to limit the risk of twin pregnancies.
There are different treatments depending on the patient's history, but above all on the origin of the anovulation or dysovulation.
ANTI-OESTROGENS: By blocking the action of oestrogens, these treatments (clomiphene citrate or Clomid®) increase the secretion of GnRH, LH and FSH by the brain. Generally speaking, this is the first-line treatment.
GONADOTROPINS: FSH is administered during the follicular phase, in the same way as for women undergoing fertility treatment. In the context of simple ovarian stimulation, this treatment is reserved for women with a satisfactory ovarian reserve. FSH stimulates the growth of ovarian follicles and prevents them from degenerating too quickly. In women with an LH deficiency, combined FSH + LH treatment is proposed.
THE GnRH PUMP: This device, placed on the patient's abdomen, releases microdoses of GnRH into the bloodstream to stimulate the release of LH and FSH by the pituitary gland. The GnRH pump is reserved for women with hypothalamic anovulation (the hypothalamus no longer releases GnRH).
METFORMIN: Obesity, diabetes or polycystic ovary syndrome can disrupt ovulation. Metformin®, which is traditionally used to treat diabetes, can restore ovulation in these patients.
Ovarian stimulation follow-up: ovarian monitoring
The hormonal ovarian stimulation phase has no precise duration: it depends on the patient's response to the treatment. Every 48 hours, the gynaecologist monitors the ovaries to ensure that this period is running smoothly. This consists of two examinations:
An ultrasound scan is used to quantify the number of growing ovarian follicles. These are also measured. In the context of MAP, ovulation is triggered when several follicles reach a size of 17 to 18 millimetres.
A blood sample is taken to measure the levels of certain hormones. Ovulation is triggered when 17β-estradiol - a reflection of follicular maturation - reaches a threshold deemed satisfactory. At the same time, LH and progesterone levels must remain low.
Depending on the results of these two medical examinations, the gynaecologist modifies the doses of hormones injected in order to optimise ovarian stimulation.
When ovarian monitoring shows optimal ovarian stimulation :
Is ovarian stimulation risky for the patient?
One of the main side effects of ovarian stimulation is an increased risk of twin pregnancy (which is potentially more difficult and more risky than a single pregnancy). There is also an increased risk of ectopic pregnancy following ovarian stimulation.
The greatest danger of ovarian stimulation remains the hyperstimulation observed when the ovary responds excessively to treatment. This is manifested by an increase in the volume of the ovaries, which contain a high number of corpora lutea. At the same time, under the effect of the gonadotropins administered during stimulation, a large number of blood vessels have formed within the ovary. These produce numerous molecules, in particular VEGF, which increase the permeability of the blood vessels. This causes fluid to leak from the blood into the peritoneum (water retention), increasing the risk of thrombosis.
Finally, hormonal treatments for ovarian stimulation can be responsible for a number of unpleasant symptoms. Typically, patients experience dizziness, fatigue, dizziness, headaches, nausea, vomiting, insomnia, hot flushes, abdominal pain, etc.
Serious complications of ovarian stimulation are rare and represent only 2% of fertility protocols
Written by:
Fabien Duval, Ph.D
Reproductive and developmental biology
Wistim
