1. BIRTH CONTROL PILLS

Birth control pills are oral contraceptives, developed originally to protect against pregnancy. Combined contraceptive pills containing estrogen and progestagen are most commonly used. They work by preventing ovulation in a woman, thinning the lining of the uterus and thickening the cervical mucus.

The role of using birth control pills in MAR procedures is synchronizing women’s cycles and making it easier to plan the next steps in the MAR process. The use of contraceptive pills is not to protect against pregnancy, but to stop the natural cycle and create an artificial, controlled cycle in a woman. Sometimes, we will start protocol with birth control pills (e.g. Lyndinette). Taking pills starts in the first days of the menstrual cycle and lasts about one month/one cycle.

Possible adverse side effects:

• breakthrough bleeding (bleeding and bloody discharge that is not a period)
• sensitive breasts, nipples
• weakness
• bloating
• headaches and migraines
• mood swings
• decline in libido

2. GnRH AGONISTS

Gonadotropin-releasing hormone (GnRH) agonists are a class of drugs that affect gonadotropins (FSH, LH, prolactin) and sex hormones. They are used for various purposes – for the treatment of infertility or in artificial insemination procedures, to reduce the level of sex hormones in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, in certain gynecological disorders such as severe premenstrual syndrome, extremely heavy menstrual bleeding, abnormal uterine bleeding, uterine leiomyomas and endometriosis and in case of high testosterone levels in women (hirsutism, acne).

The role of GnRH agonists in MAR procedures is to stop the natural production of gonadotropins and sex hormones and create a current state of hypogonadotropic hypogonadism. In this way, when adding artificial gonadotropins (FSH or FSH+LH) in the form of drugs/injections to stimulate the ovaries, the ovaries should respond much better and thus produce a greater number of follicles.

The mechanism of action

The hypothalamus is a small area at the base of the brain that secretes gonadoliberin or gonadotropin-releasing hormone (GnRH), which then stimulates the adenohypophysis to start secreting gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH stimulate the growth and maturation of follicles in the ovaries. 

GnRH agonists are stronger than endogenous (natural) GnRH and have a shorter half-life. They bind more quickly to GnRH receptors on the adenohypophysis and remain on the receptors for a longer time. At the beginning, the adenohypophysis is strongly stimulated, so that it starts to produce larger amounts of FSH and LH, but over time, due to constant stimulation, the adenohypophysis becomes desensitized and, as a result, the production of FSH and LH decreases or almost completely stops.

How are GnRH agonists administered?

In our clinic, you will most often meet GnRH agonists under the names: Suprefact (buserilin), Diphereline and Gonapeptyl (triptorelin). All medications are intended for subcutaneous administration (under the skin) with a small, short needle, but Diphereline is sometimes also available as a single, intramuscular (into a muscle) injection. Abroad, you will often be able to find these drugs in the form of a nasal spray (e.g. Suprecur) or subcutaneous implants.

Possible adverse side effects:

• hot flushes
• dry vagina
• decline in libido
• fatigue
• mood swings
• headaches

3. GONADOTROPINS

Gonadotropins are hormones that are secreted from the adenohypophysis and regulate the function of the gonads. Gonadotropic hormones include FSH, LH and prolactin. FSH and LH are the most important for all ovarian changes during the menstrual cycle. FSH, as its name suggests, is responsible for stimulating the growth of follicles within the ovaries, while LH is decisive in the maturation and initiation of ovulation of the mature follicle.

Injectable gonadotropins are a highly purified form of natural or synthetic gonadotropins. Their application, injection into the body stimulates the growth of follicles in the ovaries. Because the drugs contain higher concentrations of gonadotropins, more follicles are stimulated and grow, thereby creating and ultimately obtaining a greater number of eggs suitable for fertilization.

Gonadotropin medications are also administered subcutaneously (under the skin) with a small, short needle. These drugs cannot be taken orally, as the digestive system would destroy them. Gonadotropins are available as a powder that needs to be mixed with an injection fluid (sterile saline) before administration, or they come as pre-mixed cartridges in self-injection devices – usually a pen, similar to an insulin delivery pen. In our clinics, patients will most often encounter gonadotropins under the following names:

• Gonal F (follitropin alfa)
• Bemfola (follitropin alfa)
• Puregon (follitropin beta)
• Menopur (human menopausal gonadotropin + lutropin alfa)
• Pergoveris (follitropin alfa + lutropin alfa)

Possible adverse side effects:

•   irritation, pain, redness at the injection site
• allergic reaction (itching, rashes, in rare severe cases breathing problems)
• sensitive breasts
• headaches
• disturbances/mood swings
• fatigue
• weakness

Possible complications during therapy with gonadotropins or ovarian stimulation:

•  enlarged, sensitive, painful ovaries
•  torsion of the ovary (twisting of the ovary and/or fallopian tube)
• development of OHSS (ovarian hyperstimulation syndrome) 

4. GnRH ANTAGONISTS?

GnRH antagonists are a class of drugs that affect gonadotropins (FSH, LH, prolactin) and sex hormones. They are used for various purposes – for the treatment of infertility or in artificial insemination procedures, in the treatment of prostate cancer (they lower the level of testosterone), endometriosis, uterine leiomyomas and in some other gynecological problems.

GnRH antagonists are used in MAR procedures to prevent the premature rise of the LH hormone or to prevent premature ovulation/follicular rupture during ovarian stimulation. 

The mechanism of action

GnRH antagonists successfully compete with endogenous GnRH molecules for binding to receptors on the adenohypophysis. This leads to immediate blockade/stopping of gonadotropin secretion. GnRH antagonists are also often called blockers. 

Unlike GnRH agonists, they work immediately and do not cause an initial strong stimulation, a reaction of the adenohypophysis (there is no secretion of large amounts of gonadotropins and sex hormones). Since they are very effective, they can be included in the treatment during active stimulation of the ovaries and not a few weeks earlier, like agonists. They are used for a short time. They cause fewer side effects.

Most often used are the following:

Cetrotide (cetrorelix acetate)
Orgalutran (ganirelix acetate) 

Possible adverse side effects:

• weakness
• pain, tenderness in the ovarian area (lower abdomen, pelvis)
• headache
• vaginal bleeding
• pain and the development of a bruise in the area of ​​​​the injection
• nausea, stomach pain

5. STOP INJECTION

Stop injection is a medicine that contains β-hCG or human chorionic gonadotropin or pregnancy hormone. 

In addition to the β-hCG-based stop injection, a GnRH agonist can also be used. The latter is usually used only if there is a very high probability of developing OHSS (ovarian hyperstimulation syndrome), as the use of a GnRH agonist for this purpose is not as effective and can lead to worse results. 

The purpose of the “stop injection” is the final maturation of the oocytes before the puncture or aspiration of follicles. 

When the stop injection is applied, the eggs start dividing in the process, called meiosis. The goal of this process is to reduce the number of chromosomes from 46 to 23. Namely, only egg cells that contain the correct number of chromosomes (i.e. 23) can enable the development of a euploid – normal, healthy embryo and, consequently, a healthy child. 

How is the “stop injection” administered?

“Stop injection” represents the end of ovarian stimulation. It is applied subcutaneously when most of the follicles in the ovaries have a diameter of 15 mm or more or when the larger follicles reach sizes between 18 and 22 mm. Follicles smaller than 15 mm usually contain undeveloped, immature oocytes. Follicles larger than 22 mm often contain cells that are already overdeveloped and also useless. 

After the “stop injection”, a puncture or follicle aspiration is scheduled within 34 to 36 hours at the most. 

In our clinics, the following are most often used:

 Pregnyl (human chorionic gonadotropin)
 Ovitrelle (choriogonadotropin alfa)

Possible adverse side effects:

•   pain and tenderness at the injection site
•   abdominal/pelvic pain
•   bloating
•   weakness

6. PROGESTERONE

Progesterone is a steroid hormone that belongs to a group of hormones called progestogens. It is secreted by the corpus luteum, a temporary endocrine gland produced by the female body in the ovary after ovulation. It is the dominant hormone in the second half of the menstrual cycle (luteal phase). 

The main task of progesterone is to prepare the lining of the uterus for the reception and implantation of the embryo, calms the uterus or prevents contraction of the uterus and helps maintain pregnancy if it occurs.

In a woman’s spontaneous, ovulatory cycle, the role of progesterone production is taken over by the corpus luteum in the woman’s ovaries. In IVF procedures, certain drugs that the woman receives during stimulation affect the function of the ovaries and, consequently, the production of progesterone. For this reason, additional, replacement progesterone therapy is necessary, which the woman receives in the form of vaginal tablets (vaginal tablets, capsules) or vaginal gels. Injections given under the skin or into a muscle are also available.

Our clinics most often use the following drugs:

  Estima – vaginal capsule (progesterone)
  Utrogestan – vaginal capsule (progesterone)
  Crinone – vaginal gel (progesterone)

Progesterone therapy is usually started one day after oocyte puncture and takes it at least until the blood test. Some clinics and gynecologists advise taking it up to the 12th week of pregnancy. 

Possible adverse side effects:

• dizziness, confusion, fatigue
• mood swings, feeling irritable
• flatulence, wind
• constipation or diarrhea
• nausea, abdominal pain
• swelling of hands and feet
• headache
• sensitive breasts and nipples
• itchy and irritated vagina
• stronger discharge from the vagina