Fertility drugs and hormones
In recent years, much progress has been made in the pharmacological treatment of both male and female subfertility (that is, the difficulty in conceiving correctable with medical interventions). For example, today FSH (follicle-stimulating hormone) is produced industrially, with a technology called recombinant DNA. This made it possible to improve the purity, homogeneity and potency of the substance compared to products used in the past and obtained from FSH extracted from the urine of pregnant women. Furthermore, today FSH can be taken by subcutaneous injection at home.
Gonadotropin-releasing hormone (GnRH) antagonists are also available, which block the "natural" production of gonadotropins and are used in the treatment protocols required by assisted fertilization.
The main drugs used in assisted fertilization are:
Clomiphene citrate: it is an anti-estrogen used to stimulate the release of FSH and LH and, therefore, to favor the development of the follicles that contain the eggs.
Gonadotropine: they are mainly the follicle stimulating (FSH) and luteinizing (LH) hormones, used to stimulate follicular development. Chorionic gonadotropin (hCG) which stimulates ovulation also belongs to this category.
Gonadotropin releasing hormone (GnRH): it is used to stimulate the release, by the pituitary gland, of FSH and LH, or to obtain down-regulation of receptors and to block the natural production of FSH / LH when this is not synchronized with the phases of the cycle.
GnRH agonists (which therefore have a similar effect to GnRH).
GnRH antagonists (which have the opposite action).
Bromocriptine: used to treat hyperprolactinaemia (too high concentrations of prolactin in the blood).
Clomiphene citrate (usually referred to as clomiphene or CC) is the oldest drug and probably the most used for fertility. It is a synthetic estrogen that is administered orally and acts on the brain to stimulate the production of estrogen by the ovary. Clomiphene is used as a first-line treatment especially for women with polycystic ovary syndrome to induce controlled ovulation.
It is a synthetic analogue of estrogen. Overall, it increases the pituitary secretion of gonadotropins, particularly FSH. The treatment increases circulating levels of FSH and LH, which favor follicular development and, therefore, an increase in natural estrogen concentrations. If the treatment is effective, the follicles reach a size sufficient for ovulation, allowing fertilization.
Clomiphene is typically taken for a 5-day cycle, in tablet form, one tablet per day during the follicular phase of the menstrual cycle.
While taking the drug, you are checked by the gynecologist with a simple ultrasound that allows you to understand if and when ovulation occurs.
Clomiphene can cause some side effects such as enlarged ovary, flushing, abdominal pain, nausea or vomiting, breast pain, headache, heavy periods and sometimes acne.
Clomiphene induces ovulation in about eight out of ten women who struggle to ovulate, but this is not always useful for natural conception: a study published in Obstetrics and Gynecology has calculated that about 40 percent of women with ovulation will conceive at the end of 6 courses of therapy (therefore six months).
If the woman does not ovulate after 3-4 cycles (or if the pregnancy has not occurred after 6-12 cycles) she is considered insensitive to clomiphene citrate and the treatment is stopped. In these cases, we switch to gonadotropin therapy.
FSH and LH, the pituitary gonadotropins, are hormones essential for normal reproduction, as they stimulate the growth of ovarian follicles and, therefore, the ovulation of the mature egg. They are therefore also fundamental hormones in fertility therapy.
Therefore, both controlled ovarian stimulation (the carefully controlled induction of the development of multiple follicles) during IVF programs and the induction of ovulation in women with anovulatory infertility unresponsive to clomiphene depend on follicular stimulation with FSH , followed by induction of ovulation with human chorionic gonadotropin (hCG), which mimics the natural LH surge that occurs mid-cycle. In addition, hCG promotes the formation and functioning of the corpus luteum.
Finally, since male infertility often results from gonadotropin deficiency, therapy with these hormones is an important aspect of treatment.
Drugs that contain FSH and / or LH stimulate the ovaries to produce and release eggs.
The induction of ovulation
FSH treatment is also used in the induction of ovulation. In the induction of ovulation, the aim is to ensure the development of a single follicle for fertilization, either through normal sexual intercourse or through intrauterine insemination. (intrauterine insemination - IUI)
In assisted reproduction techniques, the aim is to grow several follicles, in order to be able to collect the eggs to be fertilized in a test tube.
Dosage variations are very frequent from cycle to cycle, as the same woman can respond very differently from month to month to stimulation with hormones.
Careful monitoring is imperative when using FSH to avoid excessive ovarian stimulation, particularly in women with polycystic ovary syndrome. Typically, the gynecologist does a series of transvaginal ultrasound scans and sometimes also a measurement of estrogen in the blood and urine.
When one or more follicles reach the size of 18-20 mm, an injection of hCG is given to induce ovulation. It is recommended to have intercourse on the day of the hCG injection and for the next two days. Alternatively, intrauterine insemination can be used.
Depending on the studies, it is estimated that 10-30% of women undergoing gonadotropin therapy experience multiple pregnancies. Over 90 percent of these pregnancies are twins. Multiple pregnancies are obviously more dangerous than single pregnancies and even twins and may depend on imperfect monitoring of the ovarian response to hormones or on the administration of hCG when too many follicles have developed.
Only well-experienced facilities keep the multiple pregnancy rate at acceptable levels (i.e. around 10%).
Asking what the rate of multiple pregnancies is among patients treated in a particular center is a patient's right and can help estimate the efficiency of the facility.
In the case of infertility due to hormonal causes, studies estimate a success rate of pharmacological treatments alone that reaches 90 percent by the age of 35 and six treatment cycles (the percentages drop significantly above the age of 35). The percentages may also be slightly lower in the case of women with polycystic ovary syndrome.
Human chorionic gonadotropin or hCG
Natural hCG, produced by the embryonic membranes that form the placenta during pregnancy, has a similar action to natural LH. Urine-extracted hCG (obtained from the urine of pregnant women) has been used extensively for many years in the treatment of infertility. A recombinant form of hCG is currently available, i.e. produced with biotechnology.
HCG is used in women both to induce ovulation in the case of simple hormonal disorders and as a treatment to induce the production of many follicles in the case of in vitro fertilization techniques.
It is used in humans to induce the production of testosterone, in order to promote the production of spermatozoa in case of male hormonal disorders or for the treatment of cryptorchidism (failure of a testicle to descend from the abdomen to the scrotum during the development of the fetus).
In women, hCG is used in high doses to induce ovulation of the mature egg from a follicle that has developed to an adequate size or to support the activity of the corpus luteum, which in turn produces the necessary hormones. at conception. In men, hCG stimulates the production of testosterone by the Leydig cells of the testes; this hormone is essential for spermatogenesis.
Injection of hCG is usually given when ultrasound of the ovary shows the development of a follicle of at least 16 mm.
The gonadotropin-releasing hormone
Gonadotropin-releasing hormone (GnRH) is the hormone produced by the hypothalamus that stimulates the pituitary to secrete both FSH and LH. It is secreted intermittently, with peaks whose magnitude and frequency vary at different times of the cycle, inducing the release of FSH or LH. There are today various synthetic (analogues) forms of GnRH, which fall into two main categories:
* GnRH agonists (usually abbreviated to GnRHa), now routinely administered to most women undergoing ovarian stimulation for in vitro fertilization.
* GnRH antagonists, a class of drugs used to delay the LH surge and avoid unplanned ovulation.
GnRH is used to stimulate the production of multiple follicles in assisted fertilization programs and to induce spermatogenesis in men with hormonal disorders. The intermittent secretion of GnRH by the hypothalamus induces the release of FSH and LH by the pituitary. This, in turn, induces the growth and development of follicles in the ovaries and the formation of sperm in the testicles.
Due to its intermittent release from the hypothalamus, GnRH must be administered with a programmable infusion pump that mimics the natural hormone secretion pattern.
In women, an ultrasound is usually done during the first course of treatment to check for ovulation. If this occurs, subsequent courses can be monitored by measuring the blood progesterone concentration on day 21 or using an LH monitoring kit to confirm ovulation.
In humans, the success of therapy is determined by measuring the blood concentrations of gonadotropins and androgens and, in the long term, by analyzing semen.
Treatment with intermittent administration of GnRH involves very high success rates (provided there is an indication), as it gives rise to ovulatory cycles in over 90 percent of women; 80 percent of women conceive within six cycles. In men, sperm count and motility become normal and testosterone levels rise during treatment.
GnRH agonists have been created in the laboratory by altering their structure to prolong their duration of action. However, these drugs were found to actually reduce gonadotropin secretion rather than increase it. Consequently, GnRH agonists are now used to suppress the natural production of gonadotropins during ovarian stimulation (cycle suppression drugs).
GnRH agonists cannot be administered orally and are available in the form of nasal spray and subcutaneous injections.
They can produce symptoms similar to those of menopause: hot flashes, dryness of the vaginal mucous membranes and loss of desire for libido.
Since cycle suppression occurs only with prolonged use, GnRH agonists are administered for at least 2–4 weeks in ovarian stimulation.
These drugs therefore produce a suppression of the release of FSH and LH by the pituitary and are used to block the LH surge and prevent unscheduled ovulations.
Bromocriptine is used in the treatment of infertility caused by excessive prolactin levels. Prolactin is normally secreted from the front of the pituitary after delivery to stimulate milk production. An abnormal secretion of prolactin can arise in the case of pituitary tumors or be of unknown origin (idiopathic hyperprolactinaemia). Regardless of the cause, increased prolactin levels induce suppression of GnRH secretion in the hypothalamus which, in turn, disrupts the release of FSH and LH.
Bromocriptine is very effective, as long as infertility is obviously due to an excess of prolactin in the blood. It manages to restore the menstrual cycle in 90 percent of women with hyperprolactinemia: 80 percent manage to conceive naturally.
Consultation by Prof Carlo Flamigni, surgeon, freelance professor in the obstetrics and gynecology clinic, member of the National Bioethics Committee.
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