Stimulation of ovulation of PCOS. Part 2.

We continue our articles about pregnancy with a diagnosis of PCOS. You can read the first part here.


In Chile, a plenary session was held in 2002, the result of which was the first summation of data on the use of CC for ovulation induction, including in PCOS. It was noted that CC can be used in PCOS as monotherapy, in combination with gonadotropins, and in case of detected insulin resistance (IR) (using Caro and HOMA indices) — with metformin (MF). The main side effects of CC remain-the risk of multiple pregnancies, ovarian hyperstimulation syndrome and ovarian cancer. Later, studies began to appear in which it was noted that CC is most often ineffective at low doses in women with PCOS and obesity, and at higher doses (> 150 mg) it is often accompanied by hyperstimulated ovarian syndrome. And in such cases, a combination of CC and MF is more effective.

The important question remains, what is the percentage of pregnancy in women with PCOS during CC treatment? It was found that the restoration of ovulation with the use of CC occurs in 80%, and pregnancy-only in 35-40% of patients. The authors themselves associated this with the antiestrogen effect of CC at the level of the endometrium and cervical mucus. In addition, 20-25% of women with PCOS are clomiphene-resistant, and, as a rule, these are women with obesity, IR and severe hyperandrogenism.

Due to the need to discuss issues and summarize data on the treatment of PCOS in Greece, an ESHRE/ASRM consensus was held in 2007, which resulted in a synthesis of the data available at that time. The first-line drug was called CC, the second-line drug was gonadotropins, the next step in case of ineffectiveness of conservative therapy is the surgical method of treatment-electrocauterization of both ovaries (ECOI). The use of MF in women with PCOS should be limited and used only in those who have been diagnosed with a violation of glucose tolerance (HTH). The insufficient number of studies conducted in the field of biguanide use does not give a complete picture of this group of drugs for ovulation induction.

PCOS

In 2009, the data of a comparative study on the use of CC, MF and their combination for ovulation induction were published. The randomized study involved 115 women who were divided into three groups. In the MF group, ovulation was achieved in 23.7%, in the CC group-in 59%, and in the combination of these drugs — in 68.4%, the birth rate was 7.9%, 15.4%, 21.1%, respectively.

Due to the lack of algorithms for the treatment of women with PCOS (taking into account age, anamnesis of the disease, the presence or absence of IR, etc.), the age of initiation of CC therapy is determined individually for each patient. In 2009, Badawy et al. published the results of a study in which they showed that the earlier a CT scan is prescribed in women with PCOS, the more pronounced the follicular growth in the ovaries, the thickness of the endometrium will be and, thus, the percentage of pregnancy will increase.

to be continued…

Stimulation of ovulation of polycystic ovary syndrome

Today we are starting a series of articles about the ovulation stimulation of polycystic ovary syndrome, we are publishing the first part.

Polycystic ovary syndrome (PCOS) is the most common form of endocrinopathy, it occurs in 5-10% of women of reproductive age and accounts for 80%, and according to some data, even 90% of all forms of hyperandrogenism.

The classic picture of PCOS, or sclerocystic ovaries, was described by Stein and Leventhal in 1935 as a syndrome of amenorrhea and enlarged ovaries, combined in 2/3 of cases with hirsutism and in every second case with obesity. However, later it was noted the existence of a wide variety of forms of the syndrome, manifested by a significant variation in the clinical picture of the disease, the endocrine profile and morphological features of the classic syndrome, in connection with which the term “polycystic ovary syndrome”was proposed. In recent years, the concept has been put forward, which has received universal approval, that the clinical manifestations associated with PCOS should be interpreted precisely as a syndrome, and not as a disease, this is a more accurate and specific term.

The etiology and pathogenesis of PCOS are still not fully understood, despite the huge number of studies devoted to this problem.

Ovulation stimulation and the Rotterdam Consensus

The final document of the Rotterdam Consensus (2003) stated that PCOS remains a diagnosis that requires the exclusion of other known disorders that manifest themselves as universal clinical signs of hyperandrogenism, and therefore can mimic and occur “under the mask” of PCOS. While PCOS itself is a syndrome of ovarian dysfunction (irregular menstruation, anovulation, infertility), the specific manifestations of which include not only hyperandrogenism, but also the “polycystic” morphology of the ovaries. Thus, for the first time, an agreement was reached on the need to give an ultrasound assessment of the size and structure of ovarian tissue a significant diagnostic criterion.

ovulation stimulation

According to the consensus, the presence of at least two of the three criteria makes it possible to verify the diagnosis of PCOS after excluding other conditions. Thus, on the one hand, in terms of examination, PCOS remains a syndrome (a complex of symptoms), the identification of which is impossible and unacceptable on the basis of the isolated presence of any single diagnostic criterion. On the other hand, a simple analysis of the pairwise combination of modern criteria allows us to draw a fundamental conclusion about the need for an expanded interpretation of the term PCOS. This is due to the additional inclusion of new clinical forms in its definition, namely: in the absence of another hyperandrogenic pathology, the diagnosis of PCOS is permissible not only in the classical course (a complete triad of signs), but also in the presence of one of three incomplete (non-classical) clinical and instrumental duets.

It is known that PCOS accounts for 56.2% of all forms of endocrine infertility. Currently, it is believed that the main ways to restore fertility in patients with PCOS should be considered assisted reproductive technologies( ART), the purpose of which is not to treat a woman, but to achieve pregnancy in a specific cycle of ovulation stimulation. The concept of ART includes not only methods of in vitro fertilization (IVF), but also conception in a natural way as a result of various methods of ovulation induction.

The leading link in the structure of assisted reproductive technologies in PCOS is the induction of ovulation. For this purpose, various medications are used individually — derivatives of chlortrianisene – clomiphene citrate (CC) and its analogues, combined oral contraceptives, gonadotropins, gonadotropin-releasing hormone analogues, insulin sensitizers, aromatase inhibitors.

The drug of choice for anovulation is considered to be CC, which was first synthesized in 1956 by WS Merrell for contraceptive purposes. Initially, CC was used for endometrial cancer during the preparation of patients for surgery, but during surgical interventions, yellow bodies in the ovaries and secretory transformation of the endometrium were accidentally discovered, which served as the basis for the use of CC as an ovulation inducer, and since 1967, the use of the drug in patients with anovulatory dysfunction began. Is CC a first-line drug for the treatment of infertility in women with PCOS? This question has arisen throughout the use of this selective estrogen receptor modulator, and there is still no clear answer: whether to use it as monotherapy or in combination with other drugs.

to be continued…

Male and female infertility

There are primary and secondary female infertility. Primary infertility is spoken of if a woman has not had a single pregnancy, despite regular sexual activity for a year in the absence of contraception, secondary – if there is a pregnancy earlier, that is, if it is impossible to conceive a child after an abortion, ectopic pregnancy, miscarriage, or the birth of a child. Voluntary infertility can be called a situation if pregnancy is undesirable and a woman is protected using contraceptives. There are also absolute infertility, when conception is impossible due to congenital pathology or irreversible changes in the woman’s body, and relative infertility, when the ability to fertilize is not impaired; in such cases, it is appropriate to talk about reduced fertility.

The inability of a mature woman’s body to conceive is due to the following reasons:

  • endocrine disorders – anovulation) – 40%;
  • tubal-peritoneal factor-30%;
  • gynecological diseases – 15-25%;
  • immunological factor – 3%;
  • unidentified factors-2-3%.

The main cause of ovarian infertility is anovulation – a violation of the menstrual cycle, as a result of which the maturation and release of the egg from the follicle does not occur. Endocrine (anovulatory) infertility can have different origins: hypothalamic, hypothalamic-pituitary, ovarian, thyroid and adrenal gland diseases, chromosomal abnormalities, violation of implantation of a fertilized egg, violation of the function of the fallopian tubes, etc.

Etiological factors of anovulatory infertility

Hypothalamic causes. Hypothalamic gonadoliberin deficiency (gonadotropin-releasing hormone-GnRH) leads to a violation of the regulation of the gonadotropic function of the pituitary gland and, accordingly, ovarian function; clinically manifested by anovulation. Violation of GnRH secretion can occur with emotional overstrain, weight loss, under the influence of medications.

Pituitary causes. Micro-and macroadenomas of the anterior pituitary lobe, prolactinomas can lead to pathological hyperprolactinemia. In all cases, if a pituitary adenoma is suspected, magnetic resonance imaging (MRI) is necessary. A slight increase in the level of prolactin, most often temporary, can occur with emotional overstrain.

Ovarian causes. There are primary and secondary ovarian insufficiency. The cause of primary ovarian insufficiency is ovarian pathology, secondary-a decrease in the secretion of GnRH in the hypothalamus or gonadotropin hormones in the adenohypophysis. Premature ovarian insufficiency may have a genetically determined, autoimmune, idiopathic, functional (weight loss, physical activity, medications) origin.

The most common cause of ovarian anovulation (female infertility) is polycystic ovary syndrome. Often, the syndrome of luteinization of a non-ovulated follicle is detected. This condition can be caused by some medications (prostaglandin synthetase inhibitors), it is often observed in endometriosis, stress, hyperandrogenism, hyperprolactinemia, inflammatory processes in the ovaries. The diagnosis is established on the basis of ultrasound (ultrasound) or laparoscopy data.

The thyroid gland and the adrenal glands. Hypothyroidism or hyperthyroidism is accompanied by a violation of the function of the pituitary gland, ovaries, which leads to anovulation. In Itsenko-Cushing’s disease and other cases of hypercortisolemia, elevated levels of testosterone and cortisol cause suppression of the gonadotropic function of the pituitary gland, as well as ovarian dysfunction, while secondary polycystic ovaries may develop.

Chromosomal abnormalities lead to amenorrhea and are also accompanied by infertility.

Violation of the implantation of a fertilized egg occurs as a result of a decrease in the level of progesterone; it can be caused by deformation of the uterine cavity with submucosal uterine fibroids.

Violation of the function of the fallopian tubes can be a consequence of inflammatory processes of the uterine appendages, which lead to a violation of the capture of the oocyte as a result of the formation of peritubar adhesions and damage to the fimbria, as well as damage to the epithelium of the tubes. The function of the fallopian tubes can be impaired with endometriosis, destructive appendicitis, suppuration after surgery on the pelvic organs or abdominal cavity.

Smoking, alcohol abuse, drug use, psychological factors, and adverse environmental effects can contribute to a decrease in fertility.

Female infertility: Diagnostics

To determine the cause of female infertility, it is necessary to study the hormonal status, conduct ultrasound of the pelvic organs, adrenal glands, analyze the physical, mental and social health of the patient and compare it with the course of the disease, as well as with the results of the treatment. The study of the quality of life allows us to optimize tactics and strategy in the treatment of women with various diseases of the reproductive system.

The following diagnostic tests are performed:

  • determination of functional changes in the ovaries and uterus;
  • detection of urogenital tract infection;
  • assessment of the state of the uterine cavity and patency of the fallopian tubes;
  • identification of an immunological conflict between spouses.

The most informative studies of the hormonal function of the ovaries are ultrasound and hormonal monitoring, supplemented by basal temperature measurement. In infertility, the examination of patients should begin with determining the level of luteinizing (LH) and follicle-stimulating (FSH) hormones in the blood. In the early follicular phase of the cycle, the level of FSH should be below 3-5 IU/l. Exceeding the standard values indicates that the biological age of the ovaries is older than the chronological age of the woman. The study of the FSH content should be carried out together with the determination of the level of estradiol, since at the concentration of estradiol above 250 pmol/l, the level of FSH decreases (by the negative feedback mechanism). To exclude polycystic ovary syndrome, the ratio of LH/FSH is additionally calculated.

To assess the state of carbohydrate metabolism, you should measure the level of glucose and insulin in the blood on an empty stomach. If necessary, a glucose tolerance test is performed. In the middle of the luteal phase of the cycle, the level of progesterone is determined (5-7 days after the basal temperature rises). The function of the thyroid gland and the level of blood prolactin are studied.

Recently, it is recommended to start the examination of patients with infertility with a study of the content of prolactin in the blood, since an increased level of prolactin is diagnosed in 20-25% of patients with infertility and various menstrual cycle disorders, and in 40-45% of them, macro – and micro-tumors of the pituitary gland are the cause of hyperprolactinemia.

Ultrasound of the pelvic organs is performed at the initial stages of examination of patients with infertility, and hysterosalpingography – in the follicular phase of the cycle.

Female infertility: Treatment of hormonal infertility

In the treatment of anovulatory infertility, clomiphene citrate or gonadotropin preparations prepared from the urine of pregnant or postmenopausal women, and in recent years – obtained by genetic engineering, are prescribed to restore fertility.

female infertility

Clomiphene citrate is an antiestrogenic drug that has the ability to bind estradiol receptors in all target organs, including the hypothalamus, at the site of GnRH synthesis, which causes an increase in the secretion of gonadotropins and especially FSH. An increase in the level of FSH stimulates the maturation of follicles in the ovaries and leads to an increase in the concentration of estradiol. By suppressing the regulatory effect of endogenous estrogens, clomiphene citrate blocks the normal feedback mechanism, which causes an increase in the frequency of cyclic GnRH secretion. The drug is prescribed from the 2nd day of the menstrual cycle for 25-50 mg or 100 mg for 5 days, and in the case of amenorrhea – from the 2nd day of the induced menstrual cycle. Patients with polycystic ovary syndrome have an increased sensitivity to drugs that stimulate ovulation, so such patients are prescribed clomiphene citrate at a dose of no more than 25-50 mg. The effectiveness of treatment is evaluated using ultrasound. From the 9th-10th day of the menstrual cycle, the diameter of the dominant follicle should be monitored, and on the 13th-14th day – the preovulatory follicle, which should have a size of 16-26 mm. If the disappearance or gradual decrease of the dominant follicle is recorded during ultrasound, ovulation has occurred. If three or more follicles with a size of 18-22 mm are detected according to ultrasound data, sexual contact should be avoided. The level of serum progesterone exceeding 20 nmol/l on the 21st day of the menstrual cycle indicates ovulation.

Currently, ovulation stimulation is recommended for no longer than 6 months, which is associated with an increased risk of ovarian cancer when taking clomiphene citrate for more than 12 months. In real practice, due to frequent dose adjustment, the drug is often used for a longer time.

Of the side effects of clomiphene citrate, hot flashes are most often noted, which occur in 10% of cases and disappear after stopping taking the drug. Sometimes, against the background of clomiphene citrate therapy, an increase in the size of the ovaries may occur. Rarely, patients note such undesirable phenomena as nausea, vomiting, depression, nervousness, fatigue, insomnia, headache, weight gain, pain in the mammary glands. When prescribing high doses of the drug to patients with polycystic ovary syndrome, the frequency of side effects increases. In the absence of the effect of the use of clomiphene citrate in such patients, laparoscopic diathermocoagulation of the ovaries or the appointment of gonadotropins is necessary.

We talked about female infertility today, we will write about male infertility in our next article, stay with us on this blog and recommend us to your friends and acquaintances. We remind you that you can also buy Clomid using our referral link, which is located in the blog header!

The mechanism of action of clomiphene and its effectiveness

Action of clomiphene: According to the hypothesis, clomiphene directly stimulates the hypothalamus-pituitary-ovary system, which in turn affects the gynothalamic-pituitary system. This hypothesis is confirmed by clinical data that have shown the possibility of increasing the release of estrogens after taking clomiphene without first increasing FSH.

This hypothesis is also confirmed in experimental studies. Thus, Smith and Doy showed that when clomiphene is added to a medium containing testosterone and placental microsomes, the production of estrogens from testosterone increases by 1.6 times. The Hammerstein data indicate the possibility of enhancing the synthesis of progesterone from acetate in the human yellow body (in vitro) with the addition of large amounts of clomiphene by activating the 3-b-ol-dehydrogenase enzyme system. At the same time, with an increase in the dose of clomiphene, the synthesis of progesterone is sharply inhibited.

According to Israel, both assumptions should be accepted as important working hypotheses; obviously, clomiphene has the possibility of a dual effect, which is confirmed by an increase in the excretion of both gonadotropins and estrogens in women with removed ovaries. This can be explained by enzyme changes in the biosynthesis of estrogens not only in the ovary, but also in the adrenal gland, which causes an increase in the synthesis of estradiol, which in turn causes the release of gonadotropins necessary for ovulation.

Currently, it is known that clomiphene increases the release of FSH and LH as a result of binding to estrogen-dependent receptors of the hypothalamus, which causes the development of a follicle in the ovary and the appearance of an estradiol peak preceding the ovulatory peak of gonadotropins. At the same time, estrogens increase the sensitivity of the pituitary gland to Gn-RH and the ovaries to gonadotropins, which leads to ovulation. A partially local effect of clomiphene on the ovary is also possible.

Action of clomiphene

Thus, clomiphene performs its biological effect mainly due to its anti-estrogenic effect, which activates the gonadotropic function of the pituitary gland. Clomiphene has found wide application for the treatment of patients with endocrine forms of infertility due to its ability to stimulate ovulation.

Clomiphene can be used in patients with mild ovarian hypofunction, an incomplete luteal phase, with dysfunctional uterine bleeding, oligomenorrhea, as well as in women with sclerocystic ovaries. Clomiphene is also used in patients with amenorrhea as a functional test before treatment with hopadotropins and in combination therapy in combination with gonadotropins. The drug is usually prescribed for 50-100 mg, starting from the 5th day of the menstrual cycle or from the 5th day from the beginning of a menstrual-like reaction caused by progesterone.

action of clomiphene

The course of treatment usually lasts 5-7 days. In the absence of an effect, the dose of clomiphene is increased to 100-200 mg per day and repeated courses of treatment are prescribed, sometimes up to 5-6. To illustrate the dependence of the effectiveness of treatment on the dose of the drug, we present data from Roland.

Most often, ovulation occurs during the first course of treatment with small doses (50 mg for 5 days). Inslcr and Lunenfeld believe that it is still necessary to prove the existence of a relationship between the dose of the drug and the level of increase in gonadotropins, as well as the frequency of ovulation. Among patients who have ovulation, the percentage of pregnancy varies between 15-30.

According to the summary data of the Merrell laboratory, which synthesized action of clomiphene for clinical use for the first time, 1,454 out of 5,569 patients (24%) had 1,654 pregnancies; 1,223 of them were full-term, and 100 women had twins or triplets. In 22% of cases, the pregnancy ended with a spontaneous abortion. This percentage is quite high if we compare these data with the number of spontaneous abortions in “healthy” women (10%). At the same time, in women who have suffered from primary infertility for a long time, the percentage of spontaneous abortions is 20, and in secondary infertility — 24.8

Thus, the frequency of spontaneous abortions in patients treated with clomiphene is approximately the same as in women suffering from infertility, when treated with other methods. According to the summary data of this laboratory, 28 out of 1938 fetuses (1.44%) had such malformations as cleavage of the upper lip and palate, polydactyly, Down’s disease, microcephaly.

Controlled Ovulation Induction (CIO)

Controlled ovulation induction: Modern approaches to the diagnosis and treatment of infertility are based on knowledge of the fundamental foundations of the physiology of the female reproductive system, suggesting a decrease in reproductive potential and the ability to conceive with increasing age. It is known that the loss of oocytes begins at the age of 27, the peak of which falls on 35-37 years. In this regard, infertility treatment should be carried out using modern methods that have proven their effectiveness in quickly and successfully achieving pregnancy.

According to the recommendations of leading professional associations and international organizations (WHO, ESHRE, ASRM, MSAR), infertility should immediately begin examination and treatment of patients in the following cases:

  1. In the absence of pregnancy for 12 months of active sexual life without contraception in patients under 35 years of age and for 6 months in patients after 35 years of age or at the age of a man over 40 years of age;
  2. Even before the end of the above terms, if there are factors that reduce fertility. These factors include: a history of tubal pregnancies involving both fallopian tubes or one fallopian tube in combination with inflammatory diseases of the pelvic organs; ovarian resection; other operations on the pelvic organs or abdominal cavity; cases of amenorrhea; when the ovarian reserve is in a state close to exhaustion (after the age of 40, after radiation treatment or chemotherapy in young women, etc.).

controlled ovulation induction

After the diagnosis of infertility, the period of examination, conservative and surgical treatment without the use of assisted reproductive technologies should not exceed two years in patients under 35 years of age and 1 year in patients after 35 years of age.

Regardless of the cause and degree of damage to the reproductive system, the formation of infertility is due to the presence of the main or a combination of the main causes. These reasons include the following conditions:

  • oocyte maturation does not occur;
  • the fallopian tubes are impassable;
  • the endometrium is not ready for embryo implantation;
  • it is not enough for fertilization to receive sperm into the uterine cavity and further into the tubes (insufficient number of sperm in the ejaculate, violation of the properties of cervical mucus, etc.).

By the beginning of conservative infertility treatment, it is necessary to exclude a severe degree of male infertility factor and tubal infertility factor, the presence of which requires the use of assisted reproductive technologies.

If the duration of treatment already exceeds one year, you should not use methods with low efficiency (for example, the appointment of clomiphene citrate, physiotherapy, IUI-insemination without ovulation induction), but switch to methods with proven high efficiency (induction of ovulation with gonadotropins, insemination with ovulation induction, laparoscopy followed by ovulation induction or controlled ovarian stimulation).

These guidelines contain new information about the use of traditional ovulation inducers, such as clomiphene citrate, but are mainly aimed at teaching the use of modern effective direct ovulation inducers.

How dangerous is the IVF program

Today we will talk about the most exciting aspects of the IVF program and, based on scientific research in recent years, we will answer possible questions.

What is the danger of ovulation stimulation? Modern features

In the past years of the revival and the beginning of the use of controlled superovulation in the implementation of IVF programs, reproductologists used high doses of gonadotropins during stimulation, sought to get as many oocytes as possible, since it was believed that this increases the chances of fertilization and obtaining embryos. As they tried to get more cells, they also tried to transfer “more” embryos.

Now the approaches have changed categorically. Currently, it has been proven that the use of high doses of gonadotropins during controlled supervovulation does not increase the chances of fertilization, leads to rapid depletion of the ovaries, has a greater number of side effects. The ovarian response to stimulation after puncture is evaluated as follows: 0 oocytes – no response, 1-2 oocytes-poor response, 3-6 oocytes-a satisfactory response, more than 7 oocytes – a good response.

It is proved that the level of ovarian response does not affect the quality of embryos in the presence of mature oocytes. However, with a satisfactory and good response, it is possible to cryopreservate a larger number of embryos without forcing a woman to undergo the ovulation stimulation procedure several times.

IVF program

With a poor answer, the scheme of “accumulation” of embryos is currently used: several ovulation stimulations are performed with minimal doses of gonadotropins and 1-2 embryos are obtained from each such program, after which the “best” embryos are cryopreserved and only then the endometrium is prepared for embryo transfer. This scheme is beneficial for its gentle effect on the ovaries of a woman, it also contributes to the production of the most mature eggs and is used mainly in women with extremely low ovarian reserve (AMH level<1 ng/ml).

Ovarian hyperstimulation syndrome, what is it and how to avoid it?

Most women suffering from infertility have heard about ovarian hyperstimulation syndrome, the fear of this complication of IVF often pushes women away from the program. Ovarian hyperstimulation syndrome (OHSS) is a condition based on the reaction of the ovaries in response to the introduction of hormonal drugs (ovulation inducers), the doses of which exceed physiological values. This condition was first described in 1930 when using the serum of foaled mares.

Ovarian hyperstimulation syndrome is characterized by a fairly wide range of clinical manifestations: from minor changes in laboratory parameters to quite serious conditions requiring hospitalization.

The main reasons for its occurrence are high doses of hormonal drugs that are used to stimulate ovulation, and with a high level of activity of the hormone estradiol, which is produced in growing follicles, high levels of the hormone hCG. The main risk group for the formation of this syndrome are girls with a diagnosis of “Polycystic ovary syndrome”, since this group has a high follicular reserve and a large number of follicles “begins to grow” during induction.

Ovarian hyperstimulation syndrome is currently a well-studied syndrome, for this reason, reproductologists around the world are trying to stimulate the ovaries using minimal hormonal load, pursuing the main goal: to get the maximum number of mature and high-quality oocytes, to avoid ovarian hyperstimulation syndrome. All patients who are preparing for the IVF program undergo a thorough examination (according to order 107n of the Russian Federation), a reproductive doctor assesses all possible risks, preventive measures are taken in the presence of risk factors for OHSS.

Women with a high risk of the syndrome are recommended to carry out an IVF protocol followed by embryo cryopreservation and embryo transfer in another cycle.

IVF program” freezing ” of embryos

The cryopreservation method allows you to save embryos for a long time, so if the IVF attempt is unsuccessful, the “saved” embryos can be used in the future. In cases where the IVF program has been successful and the pregnancy has occurred, the remaining frozen embryos can be used in the future, when the couple decides to give birth to another child. An additional advantage of the method is to reduce the number of repeated ovarian stimulation and follicle puncture, which significantly reduces the drug load on the female body.

Hormone therapy during menopause

Hormone therapy: During the menopausal transition, the restructuring of hormonal homeostasis causes a number of changes in the female body, which negatively affect the quality of life and can lead to the formation of chronic diseases.

Hormonal therapy (contraception) and prevention of unwanted pregnancy

Hormonal contraception (combined and purely gestational) is widely used in gynecological practice, and the need for its appointment for the purpose of preventing pregnancy persists until the onset of menopause. Hormonal contraceptives are based on progestins-derivatives of nortestosterone, 17-hydroxyprogesterone or spironolactone. They are used as monopreparations or in combination with estrogens (ethinyl estradiol, estradiol, etc.), the main purpose of which is to level the side effects of progestogens.

Hormonal contraceptives have many positive non-contraceptive properties. Reducing the risk of ovarian cancer directly depends on the duration of combined oral contraception, and this effect persists up to 20 years after discontinuation of the method. The same is true for reducing the risk of endometrial cancer, which correlates with the duration of use of combined oral contraceptives and is observed for more than 20 years after their withdrawal. Combined oral contraceptives also reduce the risk of colorectal cancer and, without significantly affecting the risks of other malignancies, generally reduce the cancer risk. In addition, there is evidence of proven therapeutic or preventive effects of combined hormonal contraception (CGC) in relation to a number of gynecological and extragenital diseases and conditions.

But even if there are additional indications in the instructions for the use of the contraceptive drug, hormonal contraception remains primarily a method of preventing pregnancy. Ignoring this circumstance, recommending a contraceptive to a patient who does not live a sexual life, or is absolutely unable to conceive, or who wants to become pregnant, is possible only in cases where there is no alternative way to resolve a clinically significant problem. However, it is during the menopausal transition against the background of a decrease in sexual activity and the ability to conceive that complaints of menstrual cycle disorders often appear, requiring the appointment of therapy, not contraception.

Menopausal hormone therapy and correction of menopausal disorders

The late phase of the menopausal transition begins with the prolongation of menstrual delays up to 60 days and the appearance of episodes of amenorrhea, characterized by an increase in the frequency of anovulatory cycles. The duration of this stage of reproductive aging is usually one to three years before menopause. Do not forget about stimulating ovulation with clomid. There is an opinion that the secretion of estradiol at this time steadily decreases, and the level of follicle-stimulating hormone increases. However, monitoring of hormonal indicators demonstrates their significant variability and the possibility of periodic return to the premenopausal range. Given such significant fluctuations in the secretion of follicle-stimulating hormone, it is not recommended to use the determination of its concentration in the blood to clarify the status of the reproductive system. Like the early phase of the menopausal transition, the late phase is established clinically by the appearance of intermenstrual intervals, the duration of which exceeds 60 days.

Of course, the clinical criteria for entering the menopausal transition are valid only if the initial regular rhythm of menstruation and the non-use of hormonal drugs that simulate the menstrual rhythm. If it is impossible to establish the status of the reproductive system clinically, the average population characteristics should be used, according to which the majority of women enter perimenopause after 45 years. Starting from this age, complaints of hot flashes and other vasomotor and psychosomatic symptoms signal the onset of a late phase of the menopausal transition associated with estrogen deficiency, and require MGT. There may be a reasonable objection: according to the instructions for the use of MGT drugs, they are recommended to be prescribed to women during the menopausal transition with a duration of menstruation delay of more than six months. Why do the instructions and clinical recommendations of international and expert communities contradict each other?

Thus, vasomotor and psychosomatic symptoms caused by estrogen deficiency, which not only negatively affect the quality of life, but also reflect delayed health problems, become the main starting point in solving the issue of MHT. Waiting for six months of amenorrhea to initiate MGT is advisable when a woman’s complaints are insignificant, do not violate the quality of life and, accordingly, call into question the very need for treatment.

Principles of prescribing hormone therapy

After studying the characteristics of the three types of hormone therapy and the indications for their appointment, it becomes clear that the choice of one or another of them will depend on the status of the reproductive system, evaluated clinically or, if such an approach is impossible, established presumably by the age of the patient.

Contraception will be the first in the order of use of hormone therapy methods, which is built depending on the age. Recommendations on the specifics of the primary appointment of KGC come into force when consulting women over 35 years old, that is, long before the beginning of the menopausal transition.

hormone therapy

The main concern when using hormonal contraception is the risk of thrombosis due to the action of the estrogenic component. The generalized data indicate a low frequency of thrombotic complications of KGC: the frequency of acute conditions caused by thrombosis is 6-9. 9 cases per 10,000 women per year. These conditions are usually represented by venous thromboembolism. The risk of myocardial infarction increases exclusively in women who smoke, and a twofold increase in the risk of ischemic stroke does not look so threatening due to its rarity in the population of women of fertile age (1 case per 10,000 women per year) and dependence on other factors, especially migraines.

Nevertheless, the increased risk of thrombotic complications in the older age group imposes a number of restrictions on the use of KGK, including in women who smoke or patients with migraine. In the absence of contraindications to taking KGK, only those drugs that contain estradiol or a microdose of ethinyl estradiol are suitable for primary administration. Minimizing the effect of the estrogenic component allows not only to reduce thrombotic risks, but also to reduce the likelihood of estrogen-dependent weight gain associated with fluid retention, as well as to increase the level of triglycerides entering the fat depots. Overweight is an additional risk factor for thrombosis in adult women, which deserves attention in the process of individual selection of a contraceptive.

If there are appropriate indications and there are no contraindications, drugs of sex steroid hormones and their combinations can be used in the periods of late reproduction, menopausal transition and postmenopause, providing a high quality of life and prevention of diseases associated with aging. The skillful use of this resource is really able to provide women with active longevity.

Infertile marriage

Infertile marriage is the absence of pregnancy in the spouses of childbearing age during one year of regular sexual life without contraception. The frequency of infertile marriages is 8-17% and has no tendency to decrease. Every year,2-2.5 million new cases of male and female infertility are registered in the world.

Important parameters that affect the effectiveness of infertility treatment are the age of a woman and the duration of a barren marriage.

So, if in the population of women under 30 years of age during one year of regular sexual life without protection, spontaneous pregnancy occurs in 80% of cases, before 40 years-in 25%, then after 40 years-no more than 10%.

Factors that put patients at risk for possible infertility:

  • age over 35 years;
  • the duration of infertility in this and previous marriages is more than five years;
  • miscarriage in the anamnesis;
  • neuroendocrine disorders of the menstrual cycle;
  • sexually transmitted infections that were transmitted before and during marriage; genital endometriosis;
  • repeated surgical interventions on the female genital organs, especially performed by laparotomy (removal of ovarian cysts, tuboovarial inflammatory formations, plastic of the fallopian tubes, ectopic pregnancy, myomectomy).

Such patients need an in-depth examination, even if they do not raise the issue of infertility treatment (active identification of potentially infertile married couples) when applying to a medical institution.

Algorithm of examination of women with infertility

Anamnesis: information about the number of marriages, the nature of infertility (primary/secondary), the duration of infertility, the number of pregnancies in marriages, their outcomes and complications. Features of menstrual function, menstrual cycle disorders, probable causes and duration. Analysis of previous examination and treatment, the use of contraceptives and medications that affect fertility. Extragenital diseases and surgical interventions, including gynecological; inflammatory diseases of the pelvic organs (etiological factors, features of the clinical course, the number of episodes). Features of the influence of environmental factors, occupational hazards, bad habits (alcohol, drugs).

Clinical examination: determination of the body mass index; the presence of hirsutism; the degree of development of the mammary glands and discharge from them; the state of the thyroid gland, skin and mucous membranes; assessment of the general condition, gynecological status.

TORCH-complex: determination of antibodies (immunoglobulins – Ig) G and M to rubella, toxoplasmosis, herpes simplex virus types 1 and 2, cytomegalovirus. If there are no IgG antibodies to rubella, you should be vaccinated.

infertile marriage

Ultrasound examination of the pelvic organs. Ultrasound examination of the mammary glands for all women under 36 years of age and the thyroid gland (if indicated).

Endoscopic methods: laparoscopy and hysteroscopy followed by endometrial biopsy in the presence of endometrial pathology and subsequent histological examination of scrapings

If the examination program is not fully completed, the diagnosis of infertility in a woman cannot be considered reliable, and treatment will obviously be unsuccessful. Taking clomid here will not be effective.

Algorithms for diagnosing male infertility

Anamnesis: number of marriages; primary/secondary infertility; duration of infertility; previous examination and treatment for infertility; systemic diseases (diabetes mellitus, nervous and mental diseases, tuberculosis); medicinal and other therapies affecting fertility; surgical interventions on the organs of the urogenital tract; sexually transmitted infections; congenital and acquired pathology of the reproductive system; sexual and ejaculatory dysfunction; environmental factors, occupational hazards and bad habits (smoking, alcohol, drugs).

Clinical examination: measurement of height and body weight; determination of the presence of signs of hyperandrogenism, gynecomastia; andrological examination of the genitals, inguinal region and prostate.

Additional research methods: determination of prolactin levels, follicle-stimulating hormone, testosterone; thermography of the scrotum; craniogram (if pituitary adenoma is suspected); testicular biopsy.

As a rule, the frequency of female infertility is 70-75%, male-35-40%. The combination of female and male infertility occurs in 30-35% of married couples.

Stages of therapy depending on the causes of infertile marriage

Tubal-peritoneal factor. Rehabilitation and conservative treatment (antibiotic therapy, physiotherapy, balneotherapy) for 6-12 months are subject to patients after laparoscopic correction of the adhesive process of the first-second degree according to the Hulk classification and with passable fallopian tubes. In the absence of pregnancy, repeated surgical treatment is not indicated and the couple is sent to an IVF clinic. In the presence of hydrosalpinxes, the inability to restore the patency of the fallopian tubes, the third-fourth degree of the adhesive process, the IVF program is immediately shown.

After laparoscopic removal of foci of endometriosis, endometrioid ovarian cysts and salpingo-oovariolysis (with adhesive process in the small pelvis) for three to six cycles, depending on the stage of endometriosis, progestogen therapy is carried out in a continuous mode, gonadotropin – releasing hormone agonists, danazol, estrogen-progestogenic drugs.

Infertile marriage: The male factor of infertility. Depending on the parameters of the spermogram and the results of the clinical examination of the husband, it is possible to conduct intrauterine insemination with the sperm of the husband or donor for three to six cycles against the background of ovulation stimulation in the wife. If the therapy is ineffective, IVF is indicated, often with the procedure of intracytoplasmic injection of a sperm into an egg.

A infertile marriage couple should be warned about a possible additional examination after consultation with specialists of the clinic.

Treatment of diffuse fibrocystic mastopathy

In premenopausal women, mastopathy occurs in 20 % of women. After the onset of menopause, new cysts and nodes usually do not appear, which proves the involvement of ovarian hormones in the occurrence of the disease.

Currently, it is known that malignant diseases of the mammary glands occur 3-5 times more often against the background of benign neoplasms of the mammary glands and in 30% of cases with nodular forms of mastopathy with proliferation phenomena. Therefore, in the fight against cancer, along with the early diagnosis of malignant tumors, timely detection and treatment of precancerous diseases is no less important.

There are non-proliferative and proliferative forms of mastopathy. At the same time, the risk of malignancy in the non-proliferative form is 0.86%, with moderate proliferation – 2.34%, with pronounced proliferation – 31.4%

The main role in the occurrence of fibrocystic mastopathy is assigned to dishormonal disorders in the body of a woman. It is known that the development of the mammary glands, regular cyclic changes in them in puberty, as well as changes in their function during pregnancy and lactation are influenced by a whole complex of hormones: gonadotropin-releasing hormone of the hypothalamus, gonadotropins (luteinizing and follicle-stimulating hormones), prolactin, chorionic gonadotropin, thyroid-stimulating hormone, androgens, corticosteroids, insulin, estrogens and progesterone.

Any disorders of the hormone balance are accompanied by dysplastic changes in the breast tissue. The etiology and pathogenesis of myopathy have not yet been definitively established, although more than a hundred years have passed since the description of this symptom complex. An important role in the pathogenesis is assigned to relative or absolute hyperestrogenism and progesterone deficiency. Estrogens cause the proliferation of the ductal alveolar epithelium and stroma, and progesterone counteracts these processes, ensures the differentiation of the epithelium and the cessation of mitotic activity. Progesterone has the ability to reduce the expression of estrogen receptors and reduce the local level of active estrogens, thereby limiting the stimulation of breast tissue proliferation.

Mastopathy – Hormonal imbalance

Hormonal imbalance in the breast tissues in the direction of progesterone deficiency is accompanied by edema and hypertrophy of the intra-lobular connective tissue, and the proliferation of the ductal epithelium leads to the formation of cysts.

In the development of mastopathy, an important role is played by the level of blood prolactin, which has a diverse effect on the breast tissue, stimulating metabolic processes in the epithelium of the mammary glands throughout a woman’s life. Hyperprolactinemia outside of pregnancy is accompanied by swelling, swelling, soreness and swelling in the mammary glands, more pronounced in the second phase of the menstrual cycle.

The most common cause of mastopathy is hypothalamic-pituitary diseases, thyroid disorders, obesity, hyperprolactinemia, diabetes mellitus, impaired lipid metabolism, etc.

The cause of dyshormonal disorders of the mammary glands can be gynecological diseases; sexual disorders, hereditary predisposition, pathological processes in the liver and bile ducts, pregnancy and childbirth, stressful situations. Often, mastopathy develops during menarche or menopause. In the adolescent period and in young women, the diffuse type of mastopathy with minor clinical manifestations, characterized by moderate soreness in the upper-outer quadrant of the breast, is most often detected.

mastopathy & clomid

At the age of 30-40, multiple small cysts with a predominance of the glandular component are most often detected; the pain syndrome is usually pronounced significantly. Single large cysts are most common in patients aged 35 years and older.

Fibrocystic mastopathy is also found in women with a regular two-phase menstrual cycle.

Conclusions:

In recent years, as a result of the conducted research, the need for active therapy, in which the leading place belongs to hormones, has become obvious. With the accumulation of clinical experience with the use of norplant, there were reports of its positive effect on diffuse hyperplastic processes in the mammary glands, since under the influence of the gestagenic component in the hyperplastic epithelium, not only the inhibition of proliferative activity, but also the development of decidual-like transformation of the epithelium, as well as atrophic changes in the epithelium of the glands and stroma, consistently occurs. In this regard, the use of progestogens is effective in 70 % of women with hyperplastic processes in the mammary glands. The study of the effect of norplant on the condition of the mammary glands in 37 women with diffuse mastopathy showed a decrease or cessation of pain and tension in the mammary glands. In a control study after 1 year on ultrasound or mammography, there was a decrease in the density of glandular and fibrous components due to a decrease in the areas of hyperplastic tissue, which was interpreted as a regression of hyperplastic processes in the mammary glands. In 12 women, the condition of the mammary glands remained the same. Despite the disappearance of their mastodinia, the structural tissue of the mammary glands did not undergo any changes. The most common side effect of norplant, as well as depo-provera, is a violation of the menstrual cycle in the form of amenorrhea and intermenstrual spotting. The use of oral progestogens for intermenstrual spotting and combined contraceptives for amenorrhea (for 1-2 cycles) leads to the restoration of the menstrual cycle in the vast majority of patients.

Currently, oral (tableted) progestogens are also used for the treatment of mastopathy.

There is no treatment algorithm for mastopathy. Conservative treatment is indicated for all patients with diffuse mastopathy.

Women suffer from menstrual cycle disorders and infertility

The menstrual cycle is one of the most mysterious phenomena in human biology. Why did our species develop a rhythmic ovulation that is independent of coitus? What is the biological meaning of menstrual bleeding, which is absent in other mammals? There are also more practical questions: it is known that physical and psychological stress, as well as body weight, significantly affect the menstrual cycle – but how and why does this happen? In search of answers, we turn to high-level processes – the analytical system of the hypothalamus.

The extension of the genus requires an optimal external and internal environment. A woman should be safe, have a favorable social environment, and have unrestricted access to nutrients. Otherwise, the pregnancy may be terminated or the fetus will suffer from developmental defects.

How can the body assess the many external and internal factors and make a choice: to take the risk of conception now-or to sacrifice part of the fertile time, waiting for more suitable conditions? Taking into account the complexity of the task, we can say that the choice of physiological states suitable for conception cannot be carried out by the pelvic organs. This function should be performed by an organ that “knows” the whole physiological context.

Menstrual cycle: Stress and procreation

In modern biology, the concept of “stress” means an overload of the adaptive abilities of the body. As a universal response to long-term adverse conditions, the hypothalamus increases plasma cortisol (and CSF) through the pituitary-adrenal system. In response, cortisol, among other things, suppresses the secretion of GnRH. This occurs in a variety of chronic conditions, different in nature and origin, but uniformly interpreted by the hypothalamus as stress: depression and anxiety disorders, diabetes, alcoholism, violation of the “sleep – wake” mode (working night shifts). Excess cortisol is also seen in many professional athletes.

menstrual cycle

So, the species Homo sapiens is adapted to long-distance running, in which endogenous cannabinoids enter the blood. At the dawn of human history, they made it easier to run for hours during times of migration and hunting, providing an analgesic and euphoric effect. Of course, they also inhibit the release of GnRH, since such severe trials are not combined with the prolongation of the genus. This probably explains some of the cases of amenorrhea among the runners these days.

Social and psychological stress

Human society has undergone significant changes over the last millennium. However, social distress, lifestyle changes, and information overload involve the same stressful mechanisms as the threat to physical survival.

In many mammals, females fight among themselves for resources and those partners that could provide tactical and genetic advantages to future offspring. In primates, a subordinate social position causes an increase in cortisol plasma. At the same time, the peak luteinizing hormone emissions required for ovulation are reduced. As resources decrease and aggressiveness increases within the community, conception is most promising in the dominant female. Aggression, including between close relatives, seems to play an important role in the suppression of ovulation among subordinate individuals.

Menstrual cycle and microecology of nutrition

In addition to the three main nutritional classes: proteins, fats and carbohydrates – with each meal, the human body receives microscopic doses of regulatory substances that have not nutritional, but informational value. The availability of vitamins of plant and animal origin historically included Homo sapiens in specific food chains, and the microelement composition of the environment determined favorable zones for habitation. Thus, vitamins and trace elements, whose importance is often underestimated, combine the biogeocenosis with individual physiology. The female body, constantly looking for optimal conditions for the prolongation of the genus, can not ignore such data.

Today, humanity has spread across the globe everywhere, often spending most of their lives moving. Thus, medical science is faced with the task of compensating for the change of ecological subsystems, which in market conditions is available only through the development of universal adaptive complexes. The degree of their influence is individual, because each organism is unique. However, such substitution drugs occupy their own therapeutic niche along with higher-level treatment methods.

Conclusion

It is possible that both in cases of metabolic stress and in cases of chronic psychological threats, the hypothalamus acts uniformly: it seeks to protect the body by reducing energy consumption and preventing risky pregnancy. This should be taken into account in patients with functional amenorrhea. In such cases, replacement therapy alone may not be sufficient, as it does not affect adrenal hyperfunction, body weight, and psychological problems. Even with artificially induced ovulation, subsequent pregnancy is threatened by ongoing psychological and / or metabolic stress. In other words, the full restoration of sexual function requires the correction of a fundamental problem-lifestyle.