To enhance the success of treatment, hormonal treatment (stimulation) is performed as a part of assisted reproduction methods. The stimulation will cause the ovaries to develop and grow more egg cells. Ultrasound examination is performed during the stimulation to monitor the quantity and size of the follicles in the ovaries. Follicles are cavities filled with fluid in which the egg cells develop. The character and height of the endometrium are also evaluated. At the same time, all blood hormone levels are monitored.
For ovarian stimulation, we use various hormonal medications. The basic and most used product is clomiphene citrate (Clostilbegyt). Clomiphene citrate is a nonsteroidal substance with low estrogen effects. By binding to the estrogen receptors, it blocks out natural estrogens, working as a strong antiestrogen. It stimulates the secretion gonadotrophin hormone FSH, alters the process of its secretion, thus inducing ovulation and supporting the development and maturation of the corpus luteum. It is taken in a pill form starting from the third to the fifth day of the cycle for five days. To induce ovulation, hCG hormone is applied once, followed by spontaneous sexual intercourse, insemination (IUI), or in vitro fertilization (IVF), according to the treatment plan.
If clomiphene citrate (CC) does not yield satisfactory results, it can be combined with doses of gonadotrophin hormone (FSH - follicle-stimulating hormone). FSH is the key hormone in inducing hyperovulation because it instantly stimulates follicular growth. In some treatment situations, we also use other stimulants to induce ovulation, such as antiestrogens – tamoxifen (Tamoxifen Ebewe) or aromatase inhibitors – letrozole (Femara), which are primarily used in the treatment of breast cancer.
OHSS is a syndrome with a mild to severe course. The body responds to the hormonal treatment, making it produce an excessive amount of mature follicles (pouches containing an egg ready for fertilization). Almost every woman is sensitive to hormonal treatment, and only about 1% of them require further treatment due to complications. About 20% of women have mild problems. With respect to time, doctors encounter two types of OHSS – early and late.
Early OHSS starts between days 3-7 after the application of hCG (human chorionic hormone), which induces ovulation in women. The late OHSS starts between days 12-17 after hCG application. The symptoms are attributed to the elevated levels of hCG that do not happen during normal ovulation. Symptoms include increased tissue permeability, free-flowing liquids in the abdominal, and thoracic cavities. Such a high loss of body liquids leads to lowered blood pressure and higher blood clotting, causing embolisms and thrombosis. A patient with a mild form experiences pressure in the abdominal cavity. Symptoms can get worse over time and can induce vomiting and diarrhea.
The OHSS is most of the time treated with bed rest and monitoring laboratory values. If there are severe complications associated with free-flowing liquids, the physician can decide to perform a puncture (extraction of liquids through a small opening induced by a needle). It is important to monitor laboratory values for blood clotting and, when necessary, implement an anticoagulant therapy (low molecular heparin is used). In severe cases, the patient must be hospitalized, and the organ functions need to be monitored.
The physicians' extensive experience in our center for assisted reproduction leads to effective precautions that can effectively minimize the risk of severe hyperstimulation syndrome to under 1%.
This method of hormonal stimulation is recommended predominantly for women with low ovarian response. It uses the initial effect of the analog (GnRh-α), which stimulates the ovaries during the first few days of application (the so-called flare-up effect), because of hypophysis stimulation, which creates the FSH hormone. FSH supports follicle growth in the ovaries. Thus, the actual FSH, produced in hypophysis, enhances the effect of the medication. GnRH-α (Synarel, Suprecur) is used on the first and third day of the menstrual cycle.
From the second day of the treatment, FSH injections (Fostimon, Gonal F, Puregon) are applied. If the largest follicles are approximately 16-18 mm, 10,000 IU of hCG hormone is applied to release the eggs (2 ampoules of Pregnyl administered by the intramuscular route). Eggs are extracted 34-36 hours after hCG administration. The possibility of premature ovulation is a disadvantage of this protocol. Hence, it is used mostly as an emergency solution.
This method of stimulation differs from the previous one in that the GnRH-α is administered for a longer time, and it is applied simultaneously with FSH injections. The long-term use of GnRH-α decreases the activity of the hypophysis, preventing a premature release of the eggs from the follicles.
Synarel nasal spray is used for the short protocol – indicated as one dose after 12 hours into one nostril starting on the second day of the menstrual cycle. From the third day of the cycle, gonadotropin injections are applied, usually 2-3 ampoules per day (150-225 IU). This protocol is appropriate for women with a lower ovarian response to the hormonal treatment.
GnRH-α with a long-term effect is applied (Decapeptyl depot, Dipherelin, Zoladex depot.), or the Synarel nasal spray is used daily, starting on the first or second day of menstrual bleeding. After 9-18 days, an ultrasound is performed to evaluate the endometrium. It should not be thicker than 4 mm, and the ovaries should not contain any cysts or follicles larger than 10 mm. If the endometrium is thicker than 4 mm, a blood sample is taken to determine the level of estradiol. It should not exceed 50 pg/ml. If the ultrasound imaging and estradiol levels show normal results, 2-3 ampoules of gonadotrophin can be administered daily. The consequent procedure is the same as in the short protocol. Long protocol from the luteal phase is a similar method, with the only difference being that the GnRH-α application is moved over the luteal phase of the previous cycle – before menstrual bleeding. The application usually starts between the 21st to 23rd day of the cycle.
The protocol with antagonists starts by applying injections (Puregon or Gonal F) on the second or third day of menstrual bleeding. Two to three ampoules (150-225 IU) are usually applied daily. After four to five days of treatment, an ultrasound is performed. If the follicles in the ovaries reach 14 mm, one subcutaneous injection of Cetrotide 0.25 mg or Orgalutran 0.25 mg daily can be applied every day. The rest of the procedure follows the same protocol as in all the previous types.
This applies to all protocols: Stimulation ends similarly, i.e., when the ultrasound shows that the largest follicle reached at least 18 mm in diameter. Then, the treated woman takes the human chorionic gonadotrophin (hCG). Eggs are extracted under general anesthesia 34-36 hours after hCG application (Pregnyl, Ovitrelle). Under ultrasound-guided imaging, a needle is inserted into the ovaries through the vagina. The needle is used to extract the liquid containing eggs from the follicle. Their quantity and quality are immediately after the procedure evaluated in the embryologic laboratory.
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