- Ovulation is controlled by the hormone.
- To increase the success of treatment in the methods of assisted reproduction performed hormonal stimulation (therapy).
- Controlled stimulation therapy can have side effects such as tension in the lower abdomen, hot flashes, headaches, mood swings, etc.
- Sensitive to hormonal therapy are almost all women, but only about 1% of complications requiring treatment.
Under normal conditions, woman’s body produces several egg cells every month, but only one of them matures completely. Its development and its ability to mature and to be released from an ovary (ovulation) is controlled by the pitituary gland (hypophysis) hormones – follicle stimulating hormone (FSH) and luteinizing hormone (LH).
To enhance the effectiveness of treatment, hormonal treatment (stimulation) is performed, which will cause the ovaries to develop and grow more egg cells. Ultrasound examination is performed during the stimulation to visualize and evaluate the quantity and size of the follicles in the ovaries. Follicles are cavities filled with liquid 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.
Many various hormonal medications are used for ovarian stimulation. Clomifene citrate (Clostilbegyt) is the most common and most used medication. Clomifene citrate is a non-steroid-based substance with low estrogen effects. It is chemically bound to the estrogen receptors and blocks out natural estrogens, working as a strong anti-estrogen. It also stimulates secretion of the gonadotrophin hormone FSH and alters the process of its secretion, which induces ovulation and supports the development and the growth of the corpus luteum. Clomifene citrate is taken in a pill form starting from the third to the fifth day of the cycle for five days. For ovulation induction, hCG hormone is applied, followed by a spontaneous sexual intercourse, insemination (IUI) or in-vitro (i.e., outside the body) fertilization (IVF), according to the treatment plan.
If clomifene citrate does not yield sufficient results, it can be combined with doses of gonadotrophin hormone (FSH – follicle stimulating hormone). FSH is the key hormone inducing hyperovulation because it strongly stimulates folliclular growth.
In today’s medicine, hormonal medications in the form of injections containing FSH are mostly used: FOSTIMON (FSH), MERIONAL (FSH + LH) or more modern, synthetically prepared types: MENOPUR, GONAL, PUREGON, which are more effective, have lower risk of inducing side effects, are easier to administer, but are also much more expensive.
List of stimulating protocols:
- ultra short protocol
- short protocol
- long protocol from follicular phase
- long protocol from luteal phase
- protocol with antagonists GnRh
Ultra Short Protocol
This method of hormonal stimulation is recommended predominantly for women with a low ovarian response. It uses the initial effect of an analog (the gonadotropin-releasing hormone agonist, GnRh-a), which has stimulative effects on the ovaries during the first few days (the so-called flare-up effect), because of hypophysis stimulation, which creates the FSH hormone. FSH supports follicle growth in the ovaries. Actual FSH, produced in hypophysis , makes the indicated medication more effective. GnRHa (Synarel, Suprecur) is used on the first and the 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 millimeters, 10,000 UI of hCG hormone is applied to release the eggs. Then, 34-36 hours after hCG application, an extraction of the eggs is performed. The possibility of premature ovulation is a disadvantage of this protocol and it is the reason for this protocol being used mostly as an emergency solution.
This method of stimulation is different from the previous one in that the GnRH-a is applied for a longer time and it is applied simultaneously with FSH injections. The long-term use of the GnRH-a decreases activity of the hypophysis, which should prevent a premature release of the eggs from the follicles. Synarel nasal spray is used for the short protocol, indicated as one dose every 12 hours into one nostril starting on the second day of the menstrual cycle. From the third day of the cycle, gonadotrophin injections are applied, usually 2 doses a day (150 – 280 UI). This protocol is appropriate for women with a lower ovarian response to the hormonal treatment.
Long Protocol from Follicular Phase
GnRH-a with a long-term effect is applied (Decapeptyl depot., Dipherelin, Zoladex depot.) or the Synarel nasal spray is used daily starting the first or second day of the menstrual bleeding. After 14-18 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 higher than 4 mm, blood sample is taken and the blood level of estradiol is evaluated. It should not exceed 50 pg/ml. If the ultrasound imaging and blood tests show normal results, 2-3 doses of gonadotrophine can be applied daily. Long protocol from luteal phase is a similar method, with the only difference being that the GnRH-a application is moved over to the luteal phase of the previous cycle – before menstrual bleeding. Application usually starts between the 21st to the 23rd day of the cycle.
Protocol with Antagonists
A protocol with antagonists starts by applying injections (Puregon or Gonal F) on the second or third day of menstrual bleeding. Two to three doses should be applied daily (150 – 210 UI). After 4 to 5 days of treatment, an ultrasound is performed. If the follicles in the ovaries reach 14 mm in size, one subcutaneous injection of Cetrotide 0.25 mg (or Orgalutran 0.25 mg) can be applied every day. The rest of the procedure follows the same protocol as in all other types.
This applies to all protocols: Stimulation ends if the largest follicle reaches at least 18 mm in diameter. Then, the treated woman takes the human chorionic gonadothropin (hCG) hormone. Approximately 34-36 hours after application of hCG (Pregnyl), the eggs are removed from the body under general anesthesia. Then, under ultrasound guided imaging, a special needle is used to extract the liquid containing eggs from the follicles. Their quantity and quality is then immediately evaluated in the embryologic laboratory.
Side effects of the hyper-stimulative treatment:
- hot flashes
- mood swings
- redness and irritation after injection applications
- ovarian hyperstimulation syndrome (OHSS)
Ovarian Hyperstimulation Syndrome (OHSS)
OHSS is a syndrome with low to moderate symptoms. The body reacts to the hormonal treatment, which makes it produce excessive amounts of follicles. Almost every woman is sensitive to the hormonal treatment, and only about 1% of them face serious complications during ovulation induction. About 20% of women have mild problems. With respect to time, there are two types – early and late. Early OHSS starts between days 3-7 after application of hCG, which induces ovulation. The late OHSS starts between days 12-17. Symptoms are caused mainly by the raised hCG levels that do not happen during normal ovulation. Symptoms include increased tissue permeability and free flowing liquids in the abdominal and the thoracic cavities. Such a high loss of body liquids results in lowered blood pressure and higher blood clotting, which can cause embolism and thrombosis. A patient with a milder form experiences pressure in the abdominal cavity. Symptoms can get worse over time and can induce vomiting and diarrhea.
Treatment of OHSS treatment is symptom based. Most of the time, bed rest and monitoring laboratory values are sufficient. If there are severe complications associated with free flowing liquids, the physician can decide to perform a puncture (extraction of the liquids through a small opening induced by a needle). It is important to monitor laboratory values for blood clotting and, when necessary, implement an anti-clotting therapy (low molecular heparine is used). If the case is severe, the patient needs to be hospitalized and their organ functions need to be monitored.
The extensive experience of the physicians in our center for assisted reproduction leads to effective precautions which minimize the risk of OHSS to under 1%.