Ovarian stimulation is a hormonal treatment aimed, as its name suggests, to stimulate the ovaries in order to obtain quality ovulation. This actually covers different protocols whose mechanisms differ according to the indications, but whose goal is the same: to obtain a pregnancy. Ovarian stimulation can be prescribed alone or be part of an ART protocol, particularly in the context of in vitro fertilization (IVF).

Schematically, there are two cases:

Simple ovulation induction treatment, prescribed in case of ovulation disorders (dysovulation or anovulation) due for example to overweight or obesity, polycystic ovary syndrome (PCOS) of unknown origin.

Ovarian stimulation as part of an ART protocol :

• intrauterine insemination (IUU): stimulation of ovulation (slight in this case) makes it possible to program the moment of ovulation and thus to deposit the sperm (previously collected and prepared) at the right time. cervix. The stimulation also makes it possible to obtain the growth of two follicles and thus increase the chances of success of the artificial insemination.
• IVF or IVF with intra-cytoplasmic sperm injection (ICSI): the aim of the stimulation is then to mature a larger number of mature oocytes in order to be able to take several follicles during follicular puncture, and thus increase the chances of obtaining good quality embryos by IVF.

There are different protocols of varying length, using different molecules depending on the indications. To be effective and avoid side effects, the ovarian stimulation treatment is indeed personalized.

The so-called “simple” ovulation induction

Its objective is to promote follicular growth in order to obtain the production of one or two mature oocytes. Different treatments are used depending on the patient, her age, the indication but also the practices of the practitioners:

• anti-estrogens: administered orally, clomiphene citrate acts by blocking estrogen receptors in the hypothalamus, which leads to an increase in the secretion of GnRH which in turn raises the level of FSH and then of LH . It is the first-line treatment in cases of infertility of ovulatory origin, except that of high origin (hypothalamus). There are different protocols but the classic treatment is based on 5 days of taking from the 3rd or 5th day of the cycle (1);
• gonadotropins : FSH, LH, FSH + LH or urinary gonadotropins (HMG). Administered daily during the follicular phase by the subcutaneous route, FSH aims to stimulate the growth of oocytes. The particularity of this treatment: only the cohort of follicles prepared by the ovary is stimulated. This treatment is therefore reserved for women with a sufficiently large follicle cohort. It will then give a boost to bring the follicles to maturation which usually evolve too quickly towards degeneration. It is also this type of treatment that is used upstream of IVF. There are currently 3 types of FSH: purified urinary FSH, recombinant FSH (produced by genetic engineering) and FSU with prolonged activity (used only upstream of IVF). Urinary gonadotropins (HMGs) are sometimes used in place of recombinant FSH. LH is generally used in combination with FSH, mainly in patients with LH deficiency.
• the GnRH pump is reserved for women with anovulation of high origin (hypothalamus). A heavy and expensive device, it is based on the administration of gonadorelin acetate which mimics the action of GnRH in order to stimulate the secretion of FSH and LH.
• metformin is usually used in the treatment of diabetes, but is sometimes used as an ovulation inducer in women with PCOS or overweight / obesity, to prevent ovarian hyperstimulation (2).

To assess the effectiveness of treatment, limit the risk of hyperstimulation and multiple pregnancy, ovulation monitoring with ultrasounds (to assess the number and size of growing follicles) and hormonal assays (LH, estradiol, progesterone) by blood test is set up throughout the duration of the protocol.

Sexual intercourse is scheduled during ovulation.

Ovarian stimulation in the context of ART

When ovarian stimulation takes place as part of an IVF or artificial insemination AMP protocol, the treatment takes place in 3 phases:

• the blocking phase : the ovaries are “put to rest” thanks to GnRH agonists or GnRH antagonists, which block the pituitary gland;
• the ovarian stimulation phase : Gonadotropin therapy is given to stimulate follicular growth. Ovulation monitoring allows monitoring of the correct response to treatment and follicle growth;
• onset of ovulation : when the ultrasound shows mature follicles (between 14 and 20 mm in diameter on average), ovulation is triggered with either:
  • injection of urinary (intramuscular) or recombinant (subcutaneous) HCG (chorionic gonadotropin);
  • an injection of recombinant LH. More expensive, it is reserved for women at risk of hyperstimulation.

36 hours after the hormonal trigger, ovulation takes place. The follicular puncture then takes place.

Supportive treatment of the luteal phase

To improve the quality of the endometrium and promote implantation of the embryo, treatment can be offered during the luteal phase (second part of the cycle, after ovulation), based on progesterone or derivatives: dihydrogesterone (by oral) or micronized progesterone (oral or vaginal).

The main complication of ovarian stimulation treatments is ovarian hyperstimulation syndrome (OHSS). The body responds too strongly to hormonal treatment, resulting in various clinical and biological signs of varying severity: discomfort, pain, nausea, distended abdomen, increase in ovarian volume, dyspnea, more or less severe biological abnormalities (increased hematocrit , elevated creatinine, elevated liver enzymes, etc.), rapid weight gain, and in the most severe cases, acute respiratory distress syndrome and acute renal failure (3).

Venous or arterial thrombosis sometimes occurs as a complication of severe OHSS. Risk factors are known:

• polycystic ovary syndrome
• a low body mass index
• an age of less than 30 years
• a high number of follicles
• a high concentration of estradiol, especially when using an agonist
• the onset of pregnancy (4).

A personalized ovarian stimulation protocol helps reduce the risk of severe OHSS. In some cases, preventive anticoagulant therapy may be prescribed.

Treatment with clomiphene citrate can lead to the appearance of eye disorders which will require discontinuation of treatment (2% of cases). It also increases the risk of multiple pregnancy by 8% in anovulatory patients and by 2,6 to 7,4% in patients treated for idiopathic infertility (5).

An increased risk of cancerous tumors in patients treated with ovulation inducers, including clomiphene citrate, was noted in two epidemiological studies, but the majority of the following studies did not confirm a cause and effect relationship ( 6).

The OMEGA study, including more than 25 patients who underwent ovarian stimulation as part of an IVF protocol, concluded, after more than 000 years of follow-up, that there was no risk of breast cancer in the event of ovarian stimulation. (20).