CORRECTION AND/OR ENHANCEMENT OF OVULATION

These are ovulation problems and, at the same time, they are the group with the highest chance of success when the correct treatment is applied. Women usually present with complaints of menstrual irregularity or absence of menstruation. This is because a normal menstrual cycle occurs with healthy and regular ovulation. Some women may also have complaints such as increased body hair, acne, and milk discharge from the breasts. In a woman who menstruates regularly, that is, with cycles of approximately 28 days, ovulation is also very likely to be regular, although rarely an ovulation problem may still be present.

Ovulation problems due to hormonal imbalance, such as in PCOS (Polycystic Ovary Syndrome), are very common and are usually seen together with menstrual irregularity. In addition, a markedly diminished ovarian reserve, ovarian damage after radiotherapy or chemotherapy, elevated prolactin hormone, severe psychological stress, rapid and significant weight loss or gain, and thyroid gland or adrenal gland dysfunctions can lead to ovulation problems through many different mechanisms.

The most reliable way to determine whether ovulation has occurred is to monitor the follicle by ultrasound and to observe that the follicle has “ruptured”. In addition, by checking the level of the ovulation hormone progesterone at the appropriate time of the cycle, it can be assessed whether healthy ovulation has taken place. Even in women without any problem, anovulatory cycles may occasionally occur, and therefore it is not correct to diagnose an ovulation disorder based on a single monitoring cycle. Furthermore, tests such as TSH hormone, PRL (prolactin) hormone, serum androgen levels (free testosterone, LH, DHEAS….), and FSH hormone may help in making the diagnosis.

Treatment approaches vary according to the diagnosis. If there is an early menopause, the situation is different. In overweight women, weight loss is recommended first. Monitoring with ovulation-inducing medications forms the basis of treatment.

Ovulation-inducing medications are hormone-based and are available in tablet form (clomiphene, tamoxifen, bromocriptine, letrozole, etc.) and in injectable form (HMG or FSH).

Clomiphene is the oldest fertility drug and has been in use since the 1960s. Clomiphene creates a situation in the body as if there were no estrogen hormone, and to compensate for this, it causes increased secretion of FSH and LH hormones, thereby initiating the development of the follicles, which are the sacs containing the eggs. In ovulation induction with clomiphene, it is recommended to start with 1 tablet (50 mg) daily on days 2–5 of the cycle and to continue for 5 days. In cases where there is no follicular development, the dose can be increased up to 3 tablets per day. After follicular development, ovulation can be monitored by ultrasound, and serum progesterone levels measured on days 21–23 of the cycle can also provide information. If follicular development occurs, ovulation usually takes place about one week after the last tablet. For this reason, it is recommended to have intercourse every other day for one week, starting 5 days after the last tablet. With clomiphene treatment, ovulation occurs in about 80% of women, while the pregnancy rate at the end of 6 months is around 30–50%. The twin pregnancy rate is about 10%. As for the side effects of this drug, although they are not frequently observed, they may include hot flushes, nausea, headache, and abdominal pain. Due to a possible increased risk of ovarian cancer, the total duration of clomiphene use is not recommended to exceed 12 months. If ovulation has not been achieved despite 4 months of clomiphene treatment, the medication should not be continued.

Tamoxifen works through a mechanism similar to that of clomiphene. Its use is the same. The insufficient endometrial thickness sometimes observed on ultrasound during clomiphene use is not usually seen with tamoxifen. Recently, opinions suggesting that tamoxifen is equal to or even superior to clomiphene have gained weight.

Letrozole blocks estrogen production in the ovaries and, to compensate for this, causes increased secretion of follicle-stimulating hormones from the pituitary gland in the brain. In this way, follicular development begins in the ovaries. Letrozole is usually started on day 3 of the cycle, and one (2.5 mg) or two tablets per day are taken for 5 days. In a significant proportion of women in whom follicular development or ovulation has not occurred with clomiphene treatment, a response can be obtained with letrozole.

HMG (human menopausal gonadotropin) is an injectable fertility drug that contains both FSH and LH hormones. It is obtained from the urine of menopausal women. It is used in women in whom clomiphene/letrozole treatment has failed or who do not produce their own FSH and LH hormones. These are expensive drugs that require close monitoring. The dose may vary from person to person and even from one month to another in the same person. During the 8–10 days of daily injections, ultrasound monitoring is recommended because there is a risk of development of too many follicles. The risk of multiple pregnancy is around 20%. Some women fear that stimulating the growth of many eggs with these injections will deplete their eggs and cause early menopause. However, this is not true. Normally, each month, 40–60 eggs in a woman start to grow and mature, and only one becomes mature (dominant), while the others undergo atresia, that is, they regress. With HMG treatment, some of the eggs that would normally undergo atresia are stimulated to continue to grow and develop.

FSH (follicle stimulating hormone) is a drug similar to HMG but contains only FSH. As with HMG, because there is a possibility of excessive stimulation of the ovaries, close ultrasound monitoring is recommended during treatment. Again, the risk of multiple pregnancy is around 20%, and one-third of these may be triplets or higher-order multiples. There are FSH preparations obtained from the urine of menopausal women as well as pure FSH preparations obtained by recombinant DNA technology.

LH (luteinizing hormone) is a hormone like FSH and HMG and is used together with FSH in some situations (such as hypogonadotropic hypogonadism). LH hormone is also present in HMG.

HCG (human chorionic gonadotropin) is a hormone normally secreted from the placenta and is obtained by purification from the urine of pregnant women. In ovulation treatments, administration of HCG is the final step after follicular development has been achieved with the fertility drugs mentioned above. The timing of the HCG injection is determined according to follicle size, endometrial (inner lining of the uterus) thickness, and blood estrogen levels. After HCG is given, the follicles rupture 36–48 hours later and release the egg inside.

Bromocriptine and cabergoline are drugs that do not directly stimulate follicular development but lower the level of prolactin (the milk hormone secreted from the pituitary gland). In patients with ovulation problems and elevated prolactin levels, the use of these drugs normalizes prolactin levels, ovulation begins, and pregnancy may occur. Nausea, vomiting, and dizziness are among their side effects. Starting with low doses and then increasing the dose reduces side effects.

GnRH analogues (GnRH agonists and GnRH antagonists) are drugs given to prevent spontaneous LH surges (undesired early ovulation signals during treatment) and thus to prevent possible treatment cancellations and increase treatment control. They are used during ovarian stimulation with FSH and HMG. These drugs can be administered according to different treatment protocols. Their side effects include hot flushes, vaginal dryness, mood changes, and depression.

GnRH agonists are drugs that can be started on day 3 or day 21 of the cycle and are available in subcutaneous injection or nasal spray forms.

GnRH antagonists are drugs administered subcutaneously, usually started on days 6–8 of the cycle during follicular monitoring, depending on follicular development and blood estrogen levels.