Treatment of polycystic ovaries

The main goal of polycystic ovary treatment is the restoration of full ovulation and a decrease in the degree of hyperandrogenism. Achieving it leads to the elimination of dependent clinical manifestations of the syndrome: infertility, menstrual disorders, hirsutism. This is achieved by various therapeutic agents, as well as by surgery - wedge resection of the ovaries.

Of the conservative agents, the most widely used synthetic estrogen-gestagenic preparations (SEGP) such as bisekurin, non-ovolone, ovidon, rigevidona, etc. EGGP is prescribed to inhibit the gonadotropic function of the pituitary gland to reduce elevated levels of LH. As a result, the stimulation of ovarian androgens decreases, and the binding capacity of the TESG is increased due to the estrogen component of the EGP. As a result, the androgenic inhibition of the cyclic centers of the hypothalamus decreases, and hirsutism is weakened. However, it should be noted that in rare cases, due to the progestogen component of SEHP, which is a derivative of Cig-steroids, there may be an increase in hirsutism. There is evidence that EGPP reduces the androgenic activity of the adrenal glands. There is a decrease in the volume of diurnal fluctuations of A, synchronous with cortisol; decrease in its reactivity to exogenous ACTH; decrease in the concentration of circulating DHEA sulfate. After the end of treatment, the effect of disinhibition (rebound effect) of the ovulatory function is observed, which is the ultimate goal of this therapy. As a result of treatment, as a rule, the size of the ovaries decreases. Usually, 3-6 courses of treatment are given on 1 tablet per day from the 5th to the 25th day of a spontaneous or induced cycle. In the case of amenorrhea, treatment is started after a progesterone test (1% progesterone, 1 ml IM for 6 days), or any tableted progestogen (0.005 g 2-times a day for 10 days), or abortive SEGP (1 tablet per day for 7-10 days). If there is no stimulating effect after a full course of treatment, you can take a break (1-2 months), hold a repeated, shorter course, from 2 to 4 cycles. If there is insufficient effect (preservation of hypolyutenism), intermittent treatment can be performed: 1 cycle of treatment, then 1 cycle without it, under the control of TFD. Such therapy is expedient to be carried out repeatedly. The indication for it is a decrease from the cycle to the cycle of the function of the yellow body (shortening of the II phase according to the basal temperature data). The efficacy of the use of SEGP in polycystic ovary syndrome remains low, no more than 30%. When they are used, side effects can occur: nausea, fluid retention in the body, weight gain, decreased libido. In rare cases, there is an increase in hirsutism. Contraindications for use are liver and kidney diseases, varicose veins and thrombophlebitis, a tendency to thrombosis.

In addition to EGPP, in the treatment of polycystic ovary syndrome, "pure" gestagens, for example, Norcolut, can be used. It is prescribed for 0,005-0,01 g / day from the 16th to the 25th day of the cycle. Duration of treatment from 2 to 6 months. The purpose of this therapy is the same as EGP (suppression of LH, reduction of ovarian T, rebound effect). The effectiveness of "pure" gestagens in the treatment of polycystic ovary syndrome is lower than that of combined with estrogens (less LH suppression, the binding capacity of TESG does not increase), but fewer side effects make it possible to use them quite widely, especially in combination with other agents. "Pure" gestagens are especially indicated for endometrial hyperplasia. They are appointed for a long time, for 6 courses, at 0.01 g / day. It is possible to use norkolut from the 5th to the 25th day of the cycle, but with this scheme, breakthrough uterine bleeding is often observed. Taking the drug on 0.01 g from the 16th to the 25th day is no less effective and almost does not cause side effects.

In detecting endometrial cancer, a long-term therapy with oxyprogesterone-capro- bonate (OPC) is usually carried out at 12.5% per 2 ml of v / m 2 times a week. This "oncological" dosage often leads to breakthrough bleeding, but it avoids radical surgical methods of treatment.

A genuine revolution in the possibilities of conservative therapy of polycystic ovary syndrome occurred due to the appearance in the therapeutic arsenal since 1961 of clomiphene citrate (clomid, clostilbegite). The greatest effectiveness of this drug was found precisely in the syndrome of polycystic ovaries. The frequency of stimulation of ovulation reaches 70-86%, the restoration of fertility is observed in 42-61% of cases.

Chemically, clofimene citrate (K) is a derivative of diethylstilbestrol, ie, a non-steroidal estrogen. Has a biologically weak estrogenic activity. At the same time, K is a strong anti-estrogen, which is confirmed by its high competitiveness with respect to the receptors of both endogenous and exogenous estrogens. Antiestrogenic properties appear to be basic in its therapeutic effect, i.e., it removes the stimulating effect of estrone Oi) on the tonic centers of the hypothalamus and at the same time stimulates the ovulatory release of LH from the pituitary gland. The site of Appendix K is the hypothalamus, pituitary gland, its direct action at the level of the ovaries is not ruled out. As numerous studies have shown, K is effective at a sufficient endogenous level of E2. In addition, its effectiveness depends on the level of T (the higher it is, the lower the efficiency), the ratio of LH / FSH (the closer to 1, the higher the efficiency), as well as the degree of hyperprolactinemia. To appoint 50-150, rarely 200 mg / day for 5-7 days, sometimes 10 days, starting with the 5th (rarely from the 3rd) day of the cycle. To avoid the effect of hyperstimulation, you should start the first course of treatment with a dose of 50 mg / day from the 5th to the 9th day of the cycle. Patients with obesity immediately showed 100 mg / day. In the absence of the effect of the first course of treatment, repeated courses should be repeated up to 3-6 times, gradually increasing the daily dose (but not more than 200-250 mg) and / or the duration of treatment up to 7-10 days (especially with a sharp decrease in the level FSH). The appearance of a regular menstrual-like reaction or hypolyutene cycles indicates an incomplete effect. The absence of a menstrual reaction and an increase in rectal temperature indicates ineffectiveness of the treatment. With insufficient K (hypolyutein cycles), it can be combined with the administration of a chorionic hormone (HG) at a dose of 3000-6000 units IM once or twice during the period of supposed ovulation, as judged from the temperature curve for the previous cycles. However, in the syndrome of polycystic ovaries, the additional administration of HG is not as effective as in other forms of anovulation, and in some cases may enhance hirsutism (by stimulating the ovarian stroma). Duration of treatment is individual and in some cases can reach 20 courses. After the achievement of ovulatory cycles on the background of K, a break in treatment should be made and the TFD should be monitored to maintain its effectiveness. When the action fades, repeated courses or another type of treatment are shown. A positive effect should be understood as the achievement of full ovulation and the function of the yellow body, rather than the onset of pregnancy, since some patients who have infertility in the background of normal inoculation restore infertility believe that this type of treatment does not help them. It should also be noted that often pregnancy occurs after the abolition of treatment, in the next cycle, as when taking the drug due to its anti-estrogenic properties, the structure of cervical mucus changes, which makes penetration of spermatozoa through it more difficult. It should be noted that in the case of induction of ovulation, the T level tends to decrease, and about 15% of patients report a decrease or slowing of hair growth. Combination of K with menopausal human gonadotropin and hC allows to reduce the dose of all drugs used. Described by a number of authors in the first years of the drug, the risk of ovarian hyperstimulation is clearly exaggerated. It is extremely rare and does not depend on the dose of the drug, but is determined by increased sensitivity to it. Other side effects, such as visual impairment, hair loss on the head, are infrequent and occur after discontinuation of the drug. Despite the high effectiveness of treatment of polycystic ovary syndrome, several authors believe that this action is temporary and in most patients does not lead to a stable remission. According to our data, the effect persists approximately at the same dependence as the effectiveness of treatment against T, LH / FSH and some clinical indicators.

New therapeutic possibilities were opened with the advent of drugs that possess antiandrogenic properties (cyproterone acetate-C). In 1962, F. Neumann et al. Synthesized C, which is a derivative of hydroxyprogesterone. The methyl group is of particular importance for anti-androgenic action. C competes with dihydrotestosterone (DHT) against cytoplasmic receptors, in addition, it inhibits translocation. Consequently, there is a decrease in androgenic action, i.e., the emergence of competitive antagonism in target organs. Along with anti-androgenic properties, C also exerts a pronounced gestagenic and antigonadotropic effect. The sale comes under the name androkur.

This drug is used to treat various androgen-dependent skin diseases and its appendages, in particular, with hirsutism, oily seborrhea, acne, androgenic alopecia, which occur in the syndrome of polycystic ovaries. The use of androkura in the syndrome makes it possible to obtain not only a cosmetic effect, but also to affect individual pathogenetic links, in particular, due to antigonadotropic action, it is possible to reduce the elevated level of LH and reduce ovarian T. Androkur is used in combination with estrogens (microfulline at 0.05 mg / day). In view of the fact that the preparation cumulates in adipose tissue, I. Hammerstein proposed an "inverse sequence of dosage", i.e., androkur (as a gestagen) is prescribed at the beginning of the cycle, from the 5th to the 14th day, 50-100 mg / day, and the use of estrogen blocks the reception of androkur; Ethinyl-estradiol is prescribed at 0.05 mg (from the 5th to the 25th day of the cycle). The use of such therapy for 6-9 courses can significantly reduce hirsutism, 9-12 courses are effective in androgenic alopecia. The greatest effectiveness was noted with acne. As a result of such therapy, a decrease in the size of the ovaries is also observed. The estrogen component contributes to the fall of hirsutism by increasing the binding capacity of the TESG. The drug is usually well tolerated, minor side effects (mastodinia, headaches, genital itching, decreased libido) are rare and do not pose a danger. The oppressive effect on the function of the adrenal cortex, described in children in the treatment of androkur premature sexual development, in adults with polycystic ovary syndrome is usually not observed. Contraindicated its use in thrombophlebitis, pregnancy.

Therapy with high doses of androkur is carried out during the initial period of treatment, and then, if necessary, go to the maintenance dosage. For this purpose, a diane preparation is used, with 1 tablet of which 0.05 mg of ethinyl estradiol and 2 mg of androquir are included. Diane is used according to the usual scheme for oral contraceptives: from the 5th to the 25th day of the cycle, 1 tablet per day. In the case of a belated menstrual reaction, the onset of admission can be postponed to the 3rd and even the first day of the cycle. The treatment allows them to successfully maintain the effect achieved by Androkur in a large dose. In addition, the drug can completely replace the EGPP. Their composition as progestogen includes derivatives of Cig-steroids, which can even enhance hirsutism. Contraindications and side effects of diana are the same as androkura. Our own experience confirms the rather high effectiveness of antiandrogen therapy in hirsutism of various genesis.

As an antiandrogen, veroshpiron is also used. The mechanism of its action consists in inhibition of T production at the 17-hydroxylation stage, in competitive inhibition of DHT binding to peripheral receptors, in enhancing the androgen catabolism, and in the activation of peripheral conversion of T into estrogens. Veroshpiron is prescribed in various doses, from 50 to 200 and even 300 mg / day continuously or from the 5th to the 25th day of the cycle. Often, with such a scheme appear intermenstrual bloody discharge, which can be eliminated with the administration of gestagens (norkolut, norethisterone acetate) or use veroshpiron only in the second half of the cycle. Treatment should be conducted for a long time, at least 5 months. EK Komarov points out his positive clinical effect. At the same time, the urinary excretion level of 17-CS does not change, the T content decreases, there is a significant increase in Eg and no changes in the level of progesterone in the blood. Despite the increase in the content of EG, the amount of LH and FSH in the blood does not change significantly. Rectal temperature remains monophasic. Thus, veroshpiron can be used in complex therapy of ovarian hyperandrogenism, mainly with a cosmetic purpose, to reduce hirsutism.

A special place in the treatment of the syndrome of polycystic ovaries is occupied by glucocorticoids (prednisolone, dexamethasone). The question of their use in this disease remains controversial. Domestic authors recommend the use of glucocorticoids in adrenal form of polycystic ovary syndrome - dexamethasone 1/2 ^_ 1 tablet per day. Duration of treatment varies: from 3 months to 1 year or more. Some authors suggest intermittent treatment regimens, using glucocorticoids only in the second phase of the cycle. Such a scheme contradicts the goal of treatment - instead of suppressing the androgenic function of the adrenal cortex, one can get its activation due to the rebound effect. EM Vikhlyaeva points out the effectiveness of combining clomiphene with dexamethasone in the mixed form of the polycystic ovary syndrome. Control over the effectiveness of suppression of the androgenic function of the adrenal cortex is more accurate in determining DHEA sulfate and 17-OH-progesterone in the blood than urinary excretion of 17-CS. As SS S. Ye notes, the results of corticosteroid therapy seem promising in patients with polycystic ovary syndrome with significant adrenal androgen secretion. Suppression of adrenal function should reduce the overall androgenic pool and, consequently, extraglundular estrone production. However, the problem is perhaps more difficult, since it has recently been established that corticosteroids exert selective inhibition on FSH-induced aromatase activity in rat ovarian granulosa cells in vitro. Thus, corticosteroid suppressive therapy requires a serious evaluation to determine its utility. The use of dexamethasone is recommended, mainly with the increase of DHEA sulfate.

In recent years, in connection with the often revealed moderate hyperprolactinaemia in the syndrome of polycystic ovaries, attempts have been made to use parlodel. As with other forms of ovulation disorders with hyperprolactinemia, it leads to the normalization of prolactin levels. In polycystic ovary syndrome, parlodel as a dopamine agonist may lead to a certain decrease in elevated levels of LH, which in turn contributes to a slight decrease in T. However, in general, the use of parlodel in polycystic ovary syndrome has been ineffective. At the same time, we observed after its introduction an increase in sensitivity to K. Thus, the drug may occupy a certain place in the complex treatment of polycystic ovary syndrome.

It should be mentioned the possibility of treating patients with polycystic ovary syndrome with a pergonal or MCh (75 units of FSH and 75 units of HG) in combination with HC. This therapy is directed to one of the main pathogenetic links of polycystic ovaries - stimulation of maturation of the follicle, granulosa cells and its aromatic activity. But in this issue much remains unclear. There are data that the administration of pergonal to patients with polycystic ovary syndrome causes an increase in the level of T in the blood. At the same time, there are reports of the effectiveness of this therapy, but the polycystic ovaries are hypersensitive to the pergola, with the possibility of their hyperstimulation. Treatment is carried out at 75-225 units of UHM IM per day, starting from the 3rd day of the cycle. When the preovulyatornogo level of E2 (300-700 pkg / ml) is reached, a one-day break is made, after which a high dose of HG (3000-9000 ED) is administered once, leading to ovulation of the mature follicle. With insufficient effectiveness in the following cycles, the dose of the drug can be increased. Duration of treatment - from one to several cycles. During the treatment, daily observation of the gynecologist, control of the TFD is mandatory, it is desirable to study the process of maturation of the follicle with ultrasound and to determine the level of E2 in the blood. The possibility of using a pure FSH preparation is discussed. There is information about the effective use in the syndrome of polycystic ovaries of lyuliberin for the stimulation of ovulation. However, the effect of MCH and lyuberin in polycystic ovary syndrome in general is much lower than other traditional drugs (progestins, clomiphene).

All these therapeutic agents for the treatment of polycystic ovary syndrome can be used in both the typical form of the disease and mixed forms of hyperandrogenism (against or in conjunction with glucocorticoids), as well as at atypical or central types. With central forms, there are some features of treatment. The first place in their treatment is diet therapy with a restriction of carbohydrates, fats, salts, aimed at reducing body weight. The total caloric value of the food is 1800 kcal / day (table 8). Introduce 1-2 days of shipment a week. In the detection of symptoms of increased intracranial pressure, neurological microsymptomy, phenomena of endocraniosa, a dehydration therapy is performed on the chest radiograph, including a severe salt restriction, diuretics (furosemide, triampur). Disinfectant preparations are used, such as aloe, fibs, vitreous, biyohinol No. 15-20 for 2-3 ml IM in a day. Cervical spine massage, nasal electrophoresis with group B vitamins are recommended. For a long time the question of the necessity of simultaneous connection of hormonal therapy and the possibility of operative treatment of this group of patients remained controversial. Currently, it is generally accepted that therapy with an atypical form of polycystic ovary syndrome should include a complex of the abovementioned medications with simultaneous connection of estrogen-progestational or gestagenic drugs to normalize gonadotropic function. As shown by VN Serov and AA Kozhin, an important moment in the pathogenetic picture of the disease is a pronounced phase change. Corrective medication during the first phase of neuroendocrine changes (hyperfunction of hypothalamic structures) can be effectively used for the purpose of directed influence on key systems that are in active functioning condition. At the beginning of the process, the authors recommend the use of therapeutic measures aimed at inhibiting the hypothalamus, a moderate decrease in hypothalamic-pituitary activity. To this end, it is necessary to use estrogen-progestin preparations, progestins, together with a diet, tranquilizers, B vitamins. Also recommend the means, normalizing the secretion of neurotransmitters (parlodel, diphenin).

Despite the expansion of the arsenal of modern hormone therapy for patients with polycystic ovary syndrome, the possibility of conservative treatment is limited to certain limits, the main method of treatment remains classical surgical intervention. At the present time, wedge-shaped ovarian resection is not performed, but excision of the hyperplastic central part of its medulla with maximum preservation of the cortical layer, puncture or incision of follicular cysts by the type of demedulation. Restoration of ovulation reaches 96%, fertility - 72% or more. Complete cessation of pathological hair growth was noted in 10-12% of patients. The mechanism of the positive effect of surgical treatment is still unclear. Many authors associate it with a decrease in the level of ovarian androgens, which allows breaking the vicious circle. After surgery, increased basal level of LH is reduced, the ratio of LH / FSH is normalized. According to AD Dobracheva, the effectiveness of surgical treatment is dependent on the specificity of the LH compound by interstitial tissue of polycystic ovaries: a positive effect is observed while maintaining such binding in at least one ovary.

Recently, there was an opinion that the effect of wedge resection of the ovaries was of a short-term nature, and surgical treatment was recommended in cases of infertility complaints. However, the study of catamnesis showed that the maximum positive effect occurs 2 years after the operation. As it turned out, the efficacy of surgical treatment in the older age group is lower than in young patients. Prolonged conservative treatment or expectant management leads to irreversible morphological changes in the ovaries, and in these cases, operative treatment also becomes ineffective. This factor should also be considered when assessing the feasibility of surgical treatment in central forms of the polycystic ovary syndrome, when conservative therapy is usually performed for a long time. Currently, most authors indicate that in case of inefficiency, it should not last more than 6-12 months - in these cases, surgical intervention is indicated.

Operative tactics are also dictated by the risk of developing hyperplastic conditions of the endometrium, including cancer, which Ya Bokhman considers as a late complication of a long-term untreated polycystic ovary syndrome. BI Zheleznov notes that, according to his data, the frequency of endometrial hyperplasia was 19.5%, adenocarcinoma 2.5%. Restoration of ovulation and full function of the corpus luteum as a result of surgical intervention is the prevention of endometrial cancer. Most authors recommend that at the sphenoid resection of the ovaries simultaneously perform diagnostic scraping of the uterine cavity.

With stromal ovary tecomatosis, it should be borne in mind that it is often accompanied by symptoms of the hypothalamic-pituitary syndrome. With this pathology, long-term conservative therapy is ineffective. Surgical treatment also gives a low percentage of recovery of ovarian function, but much more than drug therapy. It should also be noted that, as with various forms of the polycystic ovary syndrome, and with stromal ovary tecomatosis, treatment does not end after wedge resection. Mandatory dispensary follow-up is required, and after 3-6 months after surgery, corrective therapy is performed, for which all the same remedies can be used for self-treatment of polycystic ovary syndrome. It should be noted that, according to our data, after surgery, sensitivity to clomiphene increases. This should be remembered when choosing a dose of the drug in order to avoid ovarian hyperstimulation. Such a complex stage-by-stage therapy with dispensary observation allows to significantly increase the effectiveness of treatment of patients with polycystic ovary syndrome in general, including fertility.