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WHAT PATIENTS SHOULD KNOW ABOUT ERRORS IN THE INFERTILITY TREATMENT

Med. dr. V.Klimas.

Introduction.

Infertility is a painful problem faced by about 10–15% of families (5, 13, 18). In the developed countries of the world, the methods of infertility treatment have been rapidly improving recently, but some Lithuanian doctors-practitioners still have limited opportunities to get acquainted with the achievements in this field of medicine. As UAB Eugenijos ginekologijos klinika is approached by infertile families from all over Lithuania, who have often been treated in many medical institutions, we would like to share our thoughts on the most common unreasonably used research and outdated treatments that contradict the modern approach to endocrine reproductive system regulation. treatment . We’ve greatly simplified the text to make it as easy as possible for regular readers to understand. Unfortunately, some medical terms could not be avoided, so there is a glossary of medical terms at the end of the text. In the text, these terms are printed in italics.

  1. Estrogen use of female sex hormones at the beginning of the menstrual cycle. Occasionally, female sex hormones-estrogens are still used to stimulate ovarian function. This is a gross error because it inhibits follicular growth and the formation of the dominant follicle and artificially induces atresia in developing follicles (13, 21).
  2. Prescribing of progestogens (progesterone, norcolutol, etc.) from the 13th, 14th, 16th, etc. days of the cycle, for the treatment of luteal phase failure, </̋<<< if really not sure that ovulation already really was.

Ovulation does not necessarily occur in the middle of the cycle. It occurs 12-14 days before the next menstrual period. If the cycle is prolonged, ovulation may occur on the 18th, 22nd, or even later day of the cycle. Prescribing progestogens before ovulation inhibits ovulation and complicates the diagnosis of ovulation by increasing basal temperature and thickening. the cervical mucus shows the predominance of progestogens in the blood, which in this case entered as medication, although ovulation was suppressed.

Gestagens also make it harder for sperm to pass through the cervix by impairing mucus quality.

  1. Use of chorionic gonadotropin preparations during the follicular phase at low doses (500-1,500 UA) to stimulate ovarian function.

Chorionic gonadotropin stimulates androgen synthesis in the cells of follicles envelopes. If chorionic gonadotropin (ovidrel, ovitrelle, pregnyl, etc.) is administered before the preovulatory follicle is sufficiently mature, the androgenic medium will predominate in the follicles , i> estrogen production and FSH and LH receptors production. This blocks ovulation and causes follicular atresia . For ovulation stimulation, the administration of chorionic gonadotropin is only justified if there is a preovulatory follicle in the ovaries. It can be diagnosed ultrasound. In this case, chorionic gonadotropin is given as a single high dose, and ovulation occurs after 12 to 38 hours. Low doses are ineffective (9, 13, 16).

4.      Treatment of corpus luteum insufficiency with 19-nortestosterone derivatives and medroxyprogesterone acetate.

These derivatives are norethidron (norcollut), ethinodiol diacetate, levonorgestrel, allylestrenol (turinal) and others. is not suitable for the treatment of corpus luteum insufficiency because it also binds to androgen receptors in tissues that are sensitive to progestogens (eg uterine mucosa, embryonic tissue). i>, so it does not act as “pure” progestogens and is not suitable when there is a deficiency of corpus luteum (13, 21).

5.      Stimulation of ovarian function when blood levels of follicle-stimulating hormone are increased.

Elevated FSH (slightly lower LH) concentrations at the beginning of the menstrual cycle indicate one of two phenomena:

1.      Premature ovarian exhaustion syndrome, i.e. In the ovaries , the primary follicles end.

2.      Resistant ovarian syndrome develops when follicles are present in the ovaries but do not respond to FSH stimulation (e.g., due to receptor defect or damage).

In such cases, stimulation of ovarian function may not be effective and is not indicated (2, 11, 13, 21).

6.      Stimulation of ovarian function with drugs when it is not monitored whether treatment causes ovulation, complete corpus luteum formation, or antiestrogens do not impair the quality of cervical mucus and cervical mucosa.

When prescribing ovarian stimulants for infertility, it is important to monitor for the development of ovulation , the development of a fully functioning and sufficiently long-functioning corpus luteum , or the development of the cervix. the mucus is of “good” quality. It is also useful to monitor changes in the uterine lining (11, 13).

7.      Treatment of the so-called Stein-Levental syndrome with elevated ovarian resection, where the main symptoms are infertility, obesity and irregular menstrual cycles.

Stein-Levental syndrome, also known as polycystic ovarian syndrome, polycystic ovary disease, chronic anovulation syndrome. Ultrasound studies have shown that polycystic ovarian lesions are found in 75% of women with ovulation disorders of any origin, as well as in 25% of healthy fertile women with normal ovulation cycles. Therefore, polycystic ovarian changes seen on ultrasound are far from always a sign of disease. Ovarian resection often causes adhesions and infertility (18, 21), and its therapeutic effect occurs only when anovulation is caused by androgens produced inside the ovaries. surplus. Thus, the specific cause of anovulation , such as an increase in prolactin or obesity, needs to be identified and eliminated, and the ovaries need to be operated only in some cases and only in women who want to become pregnant after losing treatment with antiestrogens .

8.      Diagnosis and treatment of polycystic ovary syndrome, especially surgical, based solely on morphological changes of the ovaries found during ultrasound or surgery, in addition to other clinical, biochemical and hormonal examinations.

Polycystic ovarian changes do not necessarily indicate the presence of ovulation disorders. When ovulation is disrupted, polycystic ovarian changes are often the result of these changes (1, 12, 13, 20, 21, 24) rather than the cause, so polycystic ovarian changes were found during surgery or ultrasound alone. additional clinical and hormonal studies have very little clinical significance. Polycystic lesions could, at best, prompt the physician to examine the patient more closely, if necessary, and only then select the appropriate treatment.

9.      Surgical treatment of polycystic ovary syndrome when a woman is obese.

In this case, elevated ovarian resection , diathermocoagulation or laser evaporation are often ineffective because the ovulation disorder was not caused by excessive androgens . > production in the ovaries (1, 12, 13, 20, 21). Anovulation in obese women is caused by an increase in free sex hormones due to obesity and a decrease in the amount of sex hormone-binding globulin caused by insulin disorders, as well as an increase in the amount of estrogen produced in the subcutaneous tissue, and so on. Ovarian surgical trauma unnecessarily increases the possibility of postoperative adhesions and the infertility they cause. Women who are overweight are more likely to have postoperative adhesions because:

a) adipose tissue accumulates not only under the skin of the abdomen, but also in the abdominal cavity under the peritoneum, so the bowl becomes cramped for internal organs, the operative surfaces come into closer contact with each other;

b) Due to the thick abdominal wall and the ‘narrow pelvis’, the surgical technique becomes relatively less precise and the operation longer and bloodier, which increases the risk of postoperative adhesions (which, as already mentioned, also cause infertility).

10.  Surgical treatment of polycystic ovaries, where the greatest effort is made to affect the surface layer of the ovary: laser evaporation of the ovarian capsule, superficial inflammation with a diathermocoagulator, and so on.

Modern research has shown that women with polycystic ovary disease do not ovulate due to a thickened ovarian capsule, as was thought 20-20 years ago. Surgical action should be directed to the interior of the ovary in an effort to reduce the production of androgens and possibly other biologically active substances (5, 9, 12, 13, 18, 21, 24), while minimizing trauma to the surface of the ovary to prevent postoperative adhesions. It is logical to assume that surgical lasers are less suitable for this purpose than ovarian diathermocoagulation with a piercing electrode, as the effects of lasers, especially argon, neodymium, are concentrated on or very close to the evaporated object, so the ovary capsule is more vulnerable, but the tissues inside the ovary are less affected. Although it is quite difficult to compare the techniques of different laparoscopic ovarian burns, evaporations, diathermocoagulations , as a wide variety of surgical techniques are used, treatment-independent controls (3) are not used. shows that after diaterocoagulation women get pregnant more often than after ovarian laser evaporation (12, 13, 15).

11.  Use of chymographic or simple fallopian tube lavages and hydrotubations for the diagnosis and treatment of peritoneal infertility.

KThe fallopian tube is an organ with complex functions: its open end “grabs” the ovum after ovulation . The fallopian tube maintains the viability of sperm and egg before fertilization, creates the necessary microenvironment for fertilization and early ovum development, “transfers” the fertilized egg > to the uterus. The tubular permeability found during tubal lavage or hydrotubation has very little diagnostic value as it does not reflect the functional integrity of the fallopian tubes at all. This procedure is painful and is associated with some risk of complications (inflammation, development of endometriosis). Enzyme solutions (lidase, trypsin, chymotrypsin, etc.), which are often used for therapeutic hydrotubations, irritate the mucous membranes of the fallopian tubes and peritoneum, and can themselves cause aseptic inflammation of the fallopian tubes and peritoneum and cause adhesions and ovulation. For these reasons, tubal lavage and hydrotubation have long been used neither for the diagnosis nor for the conservative treatment of tubal (i.e., peritoneal) infertility.

12.  Irrational use of hormonal tests.

Pituitary , thyroid, ovary and more. hormone tests allow for a more accurate diagnosis of many reproductive disorders, but by irrationally prescribing them, they lose their clinical significance and unnecessarily waste resources and time.

The following types of errors are common:

·         Testing for serum estrogen levels, unless intended to monitor ovarian stimulation, is usually of no clinical significance.

Blood levels of estrogen change very rapidly, so the estrogen test is usually used only in cases of controlled ovarian stimulation, with estrogen gonadotropins . If it is not possible to get an answer to the estrogen test on the same day and adjust the treatment accordingly, this test is of no practical significance because the hormonal situation of the ovaries the next day (ie estrogen > secretion, follicle growth and maturation, etc.) may be significantly altered.

    • A study of follicle-stimulating and luteinizing hormone levels, when the exact date of the menstrual cycle on which the study was performed is not known , is almost of no clinical significance.

Most information is obtained when FSH and LH are examined at the beginning of the menstrual cycle, on days 3-5 of the cycle.

13.  X-ray examination of the skull when menstrual function is impaired.

Impaired menstrual function is not an indication for X-ray of the skull.

Such an examination is justified only for the selection of roughly pituitary diseased changes prior to a computed tomography examination when:

1)      increased prolactin secretion or breast discharge;

2)      when there is amenorrhea with a negative progesterone sample and with normal or low FSH and LH concentrations;

3)      when a tumor secreting a single gonodotropin is suspected (a very rare condition described almost exclusively as a tumor secreting only FSH and found only in men) (13, 21).

An X-ray of the skull when examining patients for infertility should not be the rule but the exception.

15.   “Scheduled sex” – attempting to have sex with only on “fertile days.” In the past, it was mistakenly thought that abstinence and less frequent sex could improve sperm quality. “Scheduled sex” and the calculation of fertile days cause unnecessary emotional and partner tension, can reduce the frequency of sexual intercourse and reduce the likelihood of conception. Studies have shown that the highest chances of getting pregnant are when you have sex at least every 2-3 days (7).

16.   Use of androgenic preparations to “stimulate” sperm production.

After administration of injectables, tablets, patches, etc. androgen preparations for the treatment of male infertility, androgen levels in the general circulation increase, but this not only does not stimulate impaired sperm production, but even inhibits it.

To understand the mechanism of this phenomenon, let us remember the structure and physiology of the testicle .

The testicle is covered with a layer of stiff fibrous tissue, the thin partitions of which penetrate the inside of the testicle and divide it into about 200 pyramid-shaped lobes. Inside the lobes is the testicular glandular tissue, which consists of tortuous seminal ducts and the tissue between them. There are 2-3 tortuous tubules in each lobe, which connect to each other as they approach the apex of the testicular lobes, becoming straight tubules. These – form a testicular network from which 12-15 outflow ducts pass to the testicle penile.
About 90% of the volume of an adult testicle consists of tortuous seminal ducts. There are two types of cells in their lumen: Sertoli and germinal.

From the germline cells in the lumen of the tortuous tubules form male gametes – sperm or sperm.

Sertoli cells and their interconnections surround the germ cells and developing gametes as scaffolds. When exposed to FSH and testosterone , Sertoli cells produce a variety of substances needed for germ cell development.

Inside the lobes, in the interstitial tissue between the tortuous tubules, there are small blood vessels, lymph vessels, and Leydig cells .

Leydig cells interact with LH molecules to produce testosterone , which is essential for spermatogenesis .

Testosterone levels inside the testicles are 100 times higher than testosterone levels in the general bloodstream. The mechanism for the formation of such high testosterone levels lies in the testicles themselves. From Leydig cells, testosterone first enters the meandering tubules through the basement membrane to Sertoli cells. They produce androgen binding protein (ASB). ASB maintains high local androgen concentrations in the lobes, which is necessary for spermatogenesis.

Only those testosterone molecules that remain unbound to ASB and androgen receptors in Sertoli cells enter the testicular blood vessels and, through them, into the systemic circulation and are carried around the whole body. Thus, the concentration of testosterone in the bloodstream of the whole body decreases many times due to dilution. This attenuates the inhibitory effect of testosterone on LH secretion in the pituitary (attenuates the negative feedback) and maintains the undiminished LH concentration that is necessary for proper Leydig cell stimulation and testosterone synthesis.

When androgens enter the body in the form of drugs, they primarily inhibit the secretion of LH in the pituitary gland. This reduces the stimulation of Leydig cells and therefore the synthesis of testosterone in Leydig cells. There is less testosterone binding to ASB, and local testosterone levels in the testicular segments fall sharply.

The use of exogenous androgens does not provide sufficient concentrations in the Sertoli cell environment and does not compensate for the decrease in endogenous testosterone production due to decreased LH secretion, resulting in inhibition of sperm production.

Thus, androgens prescribed as medications not only do not promote spermatogenesis , but may act as male hormonal contraceptives.

17.   Sperm-cervical mucus interaction samples (Simso-Huner, etc.) and anti-sperm antibody tests should not be used due to the lack of reliable data on their effects on fertility (7).
18.   Delaying pregnancy after using hormonal contraception to “cleanse the body” is the wrong tactic, as there is no reliable scientific evidence that sex hormones used for hormonal contraception have any negative effects on future fertility and the health of future children. . Conversely, the use of hormonal contraceptives (pills, patches, hormonal IUDs, vaginal rings, injections) may reduce the risk of infertility (14, 22) and increase the risk of pregnancy in some women with menstrual irregularities immediately after their contraceptive effects have disappeared. therefore, they are more likely to become pregnant in the first few months after using hormonal contraception (6, 14).

  1. Despite widespread claims to the contrary by the Royal College of Obstetricians and Gynecologists of the United Kingdom, WHO [2] and others. Experts say that there is no reliable scientific evidence that a safe termination of the first or any other pregnancy is associated with an increased risk of infertility or miscarriage if no complication occurs . Repeated and frequent abortions may increase the risk of complications, including those that complicate pregnancy (4, 10, 19).

20.   Use of infertility “treatment” methods based on knowledge of physiology and pathophysiology of reproductive mechanisms.

There are still doctors who try to “cure” infertility in sitting baths with sea salt, homeopathic remedies, various microclips, enzymes, suppositories with ichthyol, nettle tea, aloes extract (Aloes) and so on. injections, vitamins E, C, A, B1, B2, B6, electrophoresis with vitamins, various physiotherapy procedures, vaginal lavage with soda, vaginal “baths” with mixtures of various compositions, etc. Such “treatment” methods have nothing to do with the modern approach to infertility and the mechanisms that cause it. There is no more serious research to prove any effectiveness of these “methodologies”. This unnecessarily prolongs time and wastes money, and the unjustified use of these infertility “treatments” should be seen as charlatanism, to the detriment of patients.

 

References:

1.       Balen AH., Jacobs HS Infertility in practice. 2nd edition. New York: Churchill Livingstone, 2003: 440.

2.       Behrman J., Kistner RW, Patton GW, eds. Progress in Infertility, 3 rd ed. – Baston: – 1988. – P. 852.

3.       Cohen J. Laparoscopic procedures for treatment of infertility related to polycystic ovarian syndrome. Hum Reprod Update 1996, 2:337-44.

4.       Daling JR, Spadoni LR, Emanuel I. Fertility after contraception or abortion. Fertil Steril. 1990 Oct;54(4):559-73.

5.       Erickson GF., Danforth DR. Ovarian control of follicle development. Am J Obstet Gynecol. – 1995; 172.: 736-47.

6.       Farrow A, Hull MGR, Northstone K, Taylor H, Ford WCL, Golding J.
Prolonged use of oral contraception before a planned pregnancy is ssociated with a decreased risk of delayed conception. Human Reprod. 2002;17:2754-2761.

7.       Fertility assessment and treatment or people with fertility problems. Clinical guideline. National Collaborating Centre for Women’s and Children’s Health. Commissioned by the National Institute for Clinical Excellence. February 2004. http://www.rcog.org.uk/ 

8.       Fukaya T, Murakami T, Tamura M, Watanabe T, Terada Y, Yajima A. Laser vaporization of ovarian surface in polycystic ovary disease in reducedovarian hyperstimulation and improved pregnancy rates. Am J Obstet Gynecol 1995, 173:119-25.

9.       Gast MJ. Evaluation of clinical agents for ovulation induction. Am J Obstet Gynecol 1995; 172:753-759.

10.   Huggins GR, Cullins VE. Fertility after contraception or abortion. Fertil Steril. 1990 Oct;54(4):559-73..

11.   Imani B, Eijkemans MJ, te Velde ER, Habbema JD, Fauser BC. Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J Clin Endocrinol Metab 1998, 83:2361-2365.

12.   Klimas V., J.Ališauskas. Lėtinės anovuliacijos sindromas. Vilnius, 2001, – p.40.

13.   Klimas V. Rinktinės ginekologinės endokrinologijos temos. Vilnius, 2001, – p.112.

14.   Klimas V., Žaliūnas B. Šeimos planavimo metodai. Vadovas gydytojams.I dalis. Hormoninė kontracepcija. Vilnius, 2000, – p.123.

15.   Li TC, Saravelos H, Chow MS, Chisabingo R, Cooke ID. Factors affecting the outcome of laparoscopic ovarian drilling for polycystic ovarian syndrome in women with anovulatory infertility. Br J Obstet Gynaecol 1998, 105:338-44.

16.   Olive DL. The role of gonadotropins in ovulation induction. Am J Obstet Gynecol 1995; 172:759-765.

17.   RCOG. National Evidence-Based Clinical Guidelines The Care of Women Requesting Induced Abortion September 2004 RCOG Press: London.

18.   Rose BI. Ovarian drilling in infertile women with polysystic ovary syndrome.J Am Assoc Gynecol Laparosc 1996, 3:461-8.

19.   Safe abortions: technical and policy guidance for health care systems. Geneva. WHO. 2003.

20.   Seibel M. M. Infertility. A comprehensive text, 2nd .ed. Stamford, 1997.-P. 903.

21.   Speroff L. Fritz M. A. Clinical gynecologic endocrinology and infertility, 7 th ed. Baltimore. – 2004. – P. 1334.

22.   Stankevičius H., Klimas V. Hormonai ir kontracepcija. Metodiniai nurodymai gydytojams.Vilnius, 2000, – p. 35.

23.   Straus J.F., Steikampf M. P. Pituitary-ovarian interactions during follicular maturation and ovulation Am J Obstet Gynecol 1995, 172:726-35.

24.   Straus J.F., Barbieri R.L. Yen and Jaffe‘s reproductive endocrinology. Physiology, pathophysiology and clinical management. 5th edition. Elsevier Saunders. Philadelphia, 2004, – p.1042.

Glossary of terms

Amenorrhea – disappearance or absence of menstruation /

Androgens – Male sex hormones. Ovaries produce estrogens from androgens.

Anovulation – Ovarian dysfunction when there is no ovulation.

Antiestrogens – Clomiphene citrate and other drugs with similar effects designed to stimulate ovarian function.

Aseptic inflammation is inflammation caused by chemical, physical, or immune effects, not microorganisms.

Basement membrane – a very thin film visible only through a microscope on which epithelial cells of various epithelial structures of the body are located: e.g. vascular lining, uterine lining, ovarian follicles granular, and so on.

Diathermic coagulation – destruction of tissues with a special electric instrument.

Exogenous – Ingested from the environment, e.g. in the form of medicines.

Endogenous – formed inside the body.

Estrogens are female sex hormones produced by the ovarian follicles during the first half of the menstrual cycle . Some estrogen is also produced in subcutaneous adipose tissue and so on. places.

Follicles – vesicles in the female ovaries where female gametes oocytes develop.

Follicles – buds – The initial stage of follicular development . Only through a strong microscope are bladder-shaped, temporarily inactive formations in a woman’s ovaries from which all other stages of follicle develop.

Follicle – preovulatory – the final stage of development and maturation of the ovarian follicle when it is ready to ovulate . The follicle is then a bladder about 18-20 mm in size, filled with fluid, containing the female gamete – oocyte and granular cells.

Pituitary – A pea-sized endocrine gland under the brain that secretes follicle-stimulating, luteinizing, and several other hormones into the bloodstream.

FSH – follicle-stimulating hormone – a protein hormone released into the blood by the pituitary gland that stimulates the production of estrogen in the granular cells of the ovarian follicles

Corpus luteum or corpus luteum is a hormone-producing derivative ( progesterone, estrogen , etc.) formed in a follicle ruptured after ovulation .

Gestagens Progesterone and other female sex hormones with similar effects. Usually, progestogens eventually mature the lining of the uterus to allow pregnancy to establish itself and support the development of the pregnancy.

Uterine mucosa – The layer of tissue that lines the uterine cavity into which the embryo “lies”.

Gonadotropins – the common name for follicle-stimulating and luteinizing hormones

Grains are cells within the follicle that produce estrogens from the androgens in the first half of the menstrual cycle. and after ovulation, and progesterone.

The lining of the uterus is the inner layer of tissue that lines the uterine cavity.

Indication – Demonstration to prescribe a particular method or measure of examination or treatment to a patient.

Insulin is a hormone produced by the pancreas that regulates the uptake of sugar into cells. Insulin is also involved in the metabolism of male sex hormones androgens .

An egg is a female gamete that, when fertilized, develops a germ.

Ovarian resection – A surgery to cut out part of the ovarian tissue. LH – The luteinizing hormone pituitary is a protein hormone released into the blood that stimulates the production of male sex hormones in the testes of men and the ovaries of women. LH also promotes follicle rupture during ovulation, as well as progesterone production in the corpus luteum .

Ovaries – The female gonads inside the small pelvis. The ovaries produce female and male sex hormones and eggs .

Menstrual cycle – The period from the first day of your period to the beginning of the next period.

Oocytes – Female germ cells that develop in the follicles of the ovaries, precursors of the ova .

Ovulation is the rupture of a mature preovulatory follicle in the ovaries when the ovum is released.

Polycystic ovarian lesions – When examined on ultrasound, multiple cysts 3-10 mm in size are visible in the ovaries, i.e. fluid-filled “blisters”. It is often a symptom of no clinical significance.

Progesterone – A hormone produced by the corpus luteum that prepares the uterine lining for pregnancy and is needed to support pregnancy.

Prolactin is one of the hormones produced by the pituitary gland .

Receptors – Protein derivatives in the cells to which the corresponding hormones bind. Binding of hormone molecules to receptors initiates a chain of biochemical processes that ensure the effects of hormones in the body. E.g. FSH, t.y . follicle-stimulating hormone molecules bind to their receptors in granular follicle cells, triggering the production of female sex hormone estrogens .

Testicles ( synonym: eggs) – The male gonads in the scrotum, which produces male sex hormones and sperm .

Semen is the medical name of a male seed.

Spermatogenesis – The process of sperm formation in the body.

Sperm or, for sperm, male gametes. During fertilization, the sperm s in a woman’s body penetrates the female germ cell the egg and the genetic material of the two merges to form the genetic basis of the germ.

Testosterone is the main male sex hormone. In men, testosterone is produced by the testicles and adrenal glands. In women, the ovaries and adrenal glands.

 


[1]  angl.: Royal College of Obstetriciants and Gynaecologists – oficialus D. Britanijos akušerių ir ginekologų asociacijos pavadinimas

[2] PSO – Pasaulinė Sveikatos Organizacija (Jungtinių Tautų Organizacijos padalinys sveikatos apsaugos reikalams).

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