Treatment of polycystic ovaries

The main goal of polycystic ovary treatment is to restore full ovulation and reduce the degree of hyperandrogenism. Achieving it leads to the elimination of dependent clinical manifestations of the syndrome: infertility, menstrual irregularities, hirsutism. This is achieved by various therapeutic means, as well as surgical - wedge resection of the ovaries.

Of the conservative means, the most widely used are synthetic estrogen-gestagen drugs (SEGP) such as bisecurin, non-ovlon, ovidon, rigevidon, etc. SEGP are prescribed to inhibit the gonadotropic function of the pituitary gland to reduce the elevated level of LH. As a result, stimulation of ovarian androgens decreases, and the binding capacity of TESG increases due to the estrogenic component of SEGP. As a result, androgenic inhibition of the cyclic centers of the hypothalamus decreases, hirsutism is weakened. However, it should be noted that in rare cases, due to the gestagen component of SEGP, which is a derivative of Cig-steroids, hirsutism may increase. There is evidence that SEGP reduce the androgenic activity of the adrenal glands. A decrease in the volume of daily fluctuations of A, synchronous with cortisol; a decrease in its reactivity to exogenous ACTH; reduction of circulating DHEA sulfate concentration. After completion of treatment, a rebound effect of ovulatory function is observed, which is the ultimate goal of this therapy. As a result of treatment, the size of the ovaries usually decreases. Usually 3-6 courses of treatment are carried out, 1 tablet per day from the 5th to the 25th day of a spontaneous or induced cycle. In case of amenorrhea, treatment is started after a progesterone test (1% progesterone, 1 ml intramuscularly for 6 days) or the use of any tablet gestagen (norcolut, 0.005 g twice a day for 10 days), or an abortive course of SEHP (1 tablet per day for 7-10 days). If there is no stimulating effect after a full course of treatment, after a break (1-2 months), a repeated, shorter course of 2 to 4 cycles can be carried out. If the effect is insufficient (hypoluteinism persists), intermittent treatment can be performed: 1 treatment cycle, then 1 cycle without it, under the control of TFD. It is advisable to perform such therapy repeatedly. The indication for it is a decrease in the function of the corpus luteum from cycle to cycle (shortening of phase II according to basal temperature data). The effectiveness of SEGP in polycystic ovary syndrome remains low, no more than 30%. When using them, side effects are possible: nausea, fluid retention in the body, weight gain, decreased libido. In rare cases, increased hirsutism is observed. Contraindications for use are liver and kidney diseases, varicose veins and thrombophlebitis, a tendency to thrombosis.

In addition to SEHP, "pure" gestagens, such as Norcolut, can be used to treat polycystic ovary syndrome. It is prescribed at 0.005-0.01 g/day from the 16th to the 25th day of the cycle. The duration of treatment is from 2 to 6 months. The goal of this therapy is the same as SEHP (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 estrogens (lesser degree of LH suppression, no increase in the binding capacity of TESG), but fewer side effects allow them to be used quite widely, especially in combination with other agents. "Pure" gestagens are especially indicated for endometrial hyperplasia. They are prescribed for a long time, for 6 courses, at 0.01 g/day. It is possible to use Norcolut from the 5th to the 25th day of the cycle, but with this scheme, breakthrough uterine bleeding is often observed. Taking the drug at 0.01 g from the 16th to the 25th day is no less effective and has almost no side effects.

When endometrial cancer is detected, long-term therapy with oxyprogesterone caproate (OPC) 12.5%, 2 ml intramuscularly 2 times a week, is usually administered. This "oncological" dosage often leads to breakthrough bleeding, but allows one to avoid radical surgical treatment methods.

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

Chemically, clofimene citrate (C) is a derivative of diethylstilbestrol, i.e. a non-steroidal estrogen. It has biologically weak estrogenic activity. At the same time, C is a strong anti-estrogen, which is confirmed by its high competitiveness in relation to receptors of both endogenous and exogenous estrogens. Anti-estrogenic properties are apparently the main ones in its therapeutic action, 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 surge of LH from the pituitary gland. The site of application of C is the hypothalamus, the pituitary gland, its direct action at the level of the ovaries is not excluded. As numerous studies have shown, C is effective with a sufficient endogenous level of E2. In addition, its effectiveness depends on the T level (the higher it is, the lower the effectiveness), the LH/FSH ratio (the closer to 1, the higher the effectiveness), and the degree of hyperprolactinemia. K is prescribed at 50-150, rarely 200 mg / day for 5-7 days, sometimes 10 days, starting from the 5th (less often from the 3rd) day of the cycle. To avoid the effect of hyperstimulation, the 1st course of treatment should be started with a dose of 50 mg / day from the 5th to the 9th day of the cycle. Patients with obesity are immediately prescribed 100 mg / day. If there is no effect from the 1st course of treatment, repeated courses should be carried out up to 3-6 times, gradually increasing the daily dose (but not more than 200-250 mg) and / or the duration of treatment to 7-10 days (especially with a sharp decrease in the FSH level). The occurrence of a regular menstrual-like reaction or hypoluteal cycles indicates an incomplete effect. The absence of a menstrual reaction and an increase in rectal temperature indicates the ineffectiveness of the treatment. If K is insufficiently effective (hypoluteal cycles), it can be combined with the introduction of human chorionic hormone (hCG) at a dose of 3000-6000 IU intramuscularly once or twice during the period of expected ovulation, which is judged by the temperature curve for previous cycles. However, in polycystic ovary syndrome, additional administration of hCG is not as effective as in other forms of anovulation, and in some cases can increase hirsutism (due to stimulation of the ovarian stroma). The duration of K treatment is individual and in some cases can reach 20 courses. After achieving ovulatory cycles against the background of K, a break in treatment should be taken and its effectiveness should be monitored using TFD. If the effect fades, repeated courses or another type of treatment is indicated. A positive effect should be understood as achieving full ovulation and corpus luteum function, and not the onset of pregnancy, since some patients who remain infertile despite the restoration of normal ovulation believe that this type of treatment does not help them. It should also be noted that pregnancy often occurs after discontinuing treatment, in the next cycle, since when taking the drug, due to its antiestrogenic properties, the structure of cervical mucus changes,which complicates the penetration of sperm through it. It should be noted that in the case of ovulation induction, the T level tends to decrease, and about 15% of patients note a decrease or slowdown in hair growth. The combination of K with menopausal human gonadotropin and hCG allows you to reduce the dose of all drugs used. The danger of ovarian hyperstimulation described by a number of authors in the first years of using the drug is clearly exaggerated. It is observed extremely rarely 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 rare and disappear after stopping the drug. Despite the high efficiency of K treatment of polycystic ovary syndrome, a number of authors believe that this effect is temporary and does not lead to stable remission in most patients. According to our data, the effect persists with approximately the same dependence as the effectiveness of treatment on the level of T, LH / FSH and some clinical indicators.

New therapeutic possibilities were opened up with the advent of drugs with 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 the antiandrogenic effect. C competes with dihydrotestosterone (DHT) in relation to cytoplasmic receptors, in addition, it inhibits translocation. Consequently, there is a decrease in androgenic action, i.e. the emergence of competitive antagonism in the target organs. Along with antiandrogenic properties, C also has a pronounced gestagenic and antigonadotropic effect. It is marketed under the name androcur.

This drug is used to treat various androgen-dependent diseases of the skin and its appendages, in particular hirsutism, oily seborrhea, acne, and androgenic alopecia, which also occur in polycystic ovary syndrome. The use of androcur in the syndrome allows for not only a cosmetic effect, but also an effect on individual pathogenetic links, in particular, due to the antigonadotropic effect, it is possible to achieve a decrease in the elevated level of LH and a decrease in ovarian T. Androcur is used in combination with estrogens (microfollin at 0.05 mg / day). Due to the fact that the drug accumulates in adipose tissue, I. Hammerstein proposed a "reverse dosage sequence", i.e. androcur (as a gestagen) is prescribed at the beginning of the cycle, from the 5th to the 14th day, at 50-100 mg / day, and estrogen intake overlaps androcur intake; 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 is noted for acne. As a result of such therapy, a decrease in the size of the ovaries is also observed. The estrogen component contributes to a decrease in hirsutism due to an increase in the binding capacity of TESG. The drug is usually well tolerated, minor side effects (mastodynia, headaches, genital itching, decreased libido) are rare and do not pose a danger. The depressant effect on the function of the adrenal cortex, described in children during the treatment of premature puberty with androcur, is usually not observed in adults with polycystic ovary syndrome. Its use is contraindicated in thrombophlebitis, pregnancy.

High-dose therapy with androcur is carried out in the initial period of treatment, and then, if necessary, they switch to a maintenance dose. For this purpose, the drug Diana is used, 1 tablet of which contains 0.05 mg of ethinyl estradiol and 2 mg of androcur. Diana 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 case of a delayed menstrual reaction, the start of administration can be postponed to the 3rd or even the 1st day of the cycle. Treatment with it allows you to successfully maintain the effect achieved by androcur in a high dose. In addition, the drug can completely replace SEGP. They contain derivatives of Cig-steroids as a gestagen, which can even increase hirsutism. Contraindications and side effects for Diana are the same as for androcur. Our own experience confirms the fairly high efficiency of antiandrogen therapy for hirsutism of various origins.

Veroshpiron is also used as an antiandrogen. Its mechanism of action is to inhibit T production at the 17-hydroxylation stage, competitively inhibit DHT binding to peripheral receptors, enhance androgen catabolism, and activate peripheral T conversion to 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 this regimen, intermenstrual bleeding occurs, which can be eliminated by introducing gestagens (norcolut, norethisterone acetate) or using veroshpiron only in the second half of the cycle. The treatment should be long-term, at least 5 months. E. K. Komarov points to its positive clinical effect. In this case, the level of 17-KS excretion with urine does not change, the T content decreases, a reliable increase in EG and no changes in the level of progesterone in the blood are observed. Despite the increase in EG content, the amount of LH and FSH in the blood does not change significantly. Rectal temperature remains monophasic. Thus, veroshpiron can be used in the complex therapy of ovarian hyperandrogenism, mainly for cosmetic purposes, to reduce hirsutism.

Glucocorticoids (prednisolone, dexamethasone) occupy a special place in the therapy of polycystic ovary syndrome. The question of their use in this disease remains controversial. Domestic authors recommend the use of glucocorticoids in the adrenal form of polycystic ovary syndrome - dexamethasone 1/2 ^_ 1 tablet per day. The 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 regimen contradicts the purpose of treatment - instead of suppressing the androgenic function of the adrenal cortex, it is possible to achieve its activation due to the rebound effect. E. M. Vikhlyaeva points to the effectiveness of a combination of clomiphene and dexamethasone in the mixed form of polycystic ovary syndrome. The effectiveness of adrenal androgen suppression is more accurately monitored by measuring DHEA sulfate and 17-OH-progesterone in the blood than by urinary 17-CS excretion. As noted by SS C. Ye, the results of corticosteroid therapy seem encouraging in patients with polycystic ovary syndrome with significant adrenal androgen secretion. Adrenal suppression should reduce the total androgen pool and, consequently, extraglandular estrone production. However, the problem may be more complex, since corticosteroids have recently been shown to selectively inhibit FSH-induced aromatase activity in rat ovarian granulosa cells in vitro. Thus, corticosteroid suppressive therapy requires careful evaluation to determine its usefulness. Dexamethasone is recommended, mainly when DHEA sulfate is elevated.

In recent years, attempts have been made to use parlodel in connection with the frequently detected moderate hyperprolactinemia in polycystic ovary syndrome. As with other forms of ovulation disorders with hyperprolactinemia, it leads to normalization of prolactin levels. In polycystic ovary syndrome, parlodel as a dopamine agonist can also lead to some decrease in the elevated LH level, which in turn contributes to some decrease in the T level. However, in general, the use of parlodel in polycystic ovary syndrome turned out to be ineffective. At the same time, we observed an increase in sensitivity to K after its administration. Thus, the drug can occupy a certain place in the complex therapy of polycystic ovary syndrome.

It is worth mentioning the possibility of treating patients with polycystic ovary syndrome with pergonal or MCG (75 U FSH and 75 U hCG) in combination with hCG. This therapy is aimed at one of the main pathogenetic links of polycystic ovaries - stimulation of follicle maturation, granulosa cells and its aromatose activity. But much remains unclear in this matter. There is evidence that the introduction of pergonal to patients with polycystic ovary syndrome causes an increase in the T level in the blood. At the same time, there are reports of the effectiveness of this therapy, but hypersensitivity of polycystic ovaries to pergonal with the possibility of their hyperstimulation is noted. Treatment is carried out with 75-225 U MCG intramuscularly daily, starting from the 3rd day of the cycle. When the preovulatory level of E2 (300-700 pg/ml) is reached, a one-day break is taken, after which a high dose of hCG (3000-9000 U) is administered once, leading to ovulation of the mature follicle. If the effectiveness is insufficient, the dose of the drug can be increased in the following cycles. The duration of treatment is from one to several cycles. During treatment, daily observation by a gynecologist, TFD control are mandatory, a study of the follicle maturation process using ultrasound and determination of the E2 level in the blood are desirable. The possibility of using a pure FSH drug is discussed. There is information on the effective use of luliberin in polycystic ovary syndrome for ovulation stimulation. However, the effect of MCG and luliberin in polycystic ovary syndrome is generally much lower than that of other traditional agents (progestins, clomiphene).

All the above-mentioned therapeutic agents for treating polycystic ovary syndrome can be used for both the typical form of the disease and mixed forms of hyperandrogenism (against the background of or together with glucocorticoids), as well as atypical or central types. There are some treatment features for central forms. The first place in their treatment is occupied by diet therapy with restriction of carbohydrates, fats, salt, aimed at reducing body weight. The total caloric content of food is 1800 kcal / day (table 8). 1-2 fasting days are introduced per week. If symptoms of increased intracranial pressure, neurological microsymptomatology, endocraniosis phenomena are detected on an X-ray of the skull, dehydration therapy is carried out, including a sharp restriction of salt, diuretics (furosemide, triampur). Resorptive drugs are used, such as aloe, fibs, vitreous body, biyoquinol No. 15-20, 2-3 ml intramuscularly every other day. Massage of the cervical spine, nasal electrophoresis with B vitamins are recommended. For a long time, the question of the need for simultaneous use of hormonal therapy and the possibility of surgical treatment of this group of patients remained controversial. Currently, it is generally accepted that therapy for an atypical form of polycystic ovary syndrome should include a complex of the above-mentioned therapeutic agents with the simultaneous use of estrogen-gestagen or gestagen drugs to normalize gonadotropic function. As V. N. Serov and A. A. Kozhin showed, an important point in the pathogenetic picture of the disease is the pronounced phasic nature of changes. Corrective drug intervention during the first phase of neuroendocrine shifts (hyperfunction of hypothalamic structures) can be effectively used for the purpose of targeted impact on key systems in a state of active functioning. At the beginning of the process, the authors recommend the use of therapeutic measures aimed at inhibiting the hypothalamus, moderate reduction in hypothalamic-pituitary activity. For this purpose, it is necessary to use estrogen-gestagen drugs, progestins along with diet, tranquilizers, and B vitamins. Drugs that normalize the secretion of neurotransmitters (parlodel, diphenin) are also recommended.

Despite the expansion of the arsenal of modern hormonal therapy for patients with polycystic ovary syndrome, the possibilities of conservative treatment are limited to certain limits, the main method of treatment remains classical surgical intervention. Currently, not wedge resection of the ovary is performed, but excision of the hyperplastic central part of its medulla with maximum preservation of the cortex, with puncture or incision of follicular cysts by the demedulation type. Restoration of ovulation reaches 96%, fertility - 72% and more. Complete cessation of pathological hair growth is noted in 10-12% of patients. The mechanism of the positive effect of surgical treatment remains unclear to date. Many authors associate it with a decrease in the level of ovarian androgens, which helps to break the vicious circle. After surgery, the increased basal level of LH decreases, the LH/FSH ratio is normalized. According to A. D. Dobracheva, the effectiveness of surgical treatment depends on the specificity of the connection of LH with the interstitial tissue of polycystic ovaries: a positive effect is observed when such a connection is maintained in at least one ovary.

Recently, there was an opinion that the effect of wedge resection of the ovaries is short-term, and surgical treatment was recommended for complaints of infertility. However, a study of the follow-up showed that the maximum positive effect occurs 2 years after the operation. As it turned out, the effectiveness of surgical treatment in the older age group is lower than in younger patients. Long-term conservative treatment or expectant tactics lead to irreversible morphological changes in the ovaries, and in these cases, surgical treatment also becomes ineffective. This factor should apparently be taken into account when assessing the feasibility of surgical treatment for central forms of polycystic ovary syndrome, when, as a rule, conservative therapy is carried out for a long time. Currently, most authors indicate that in case of ineffectiveness, it should not last longer than 6-12 months - in these cases, surgical intervention is indicated.

The surgical tactics are also dictated by the risk of developing hyperplastic conditions of the endometrium, including cancer, which Ya. V. Bohman considers as a late complication of long-standing untreated polycystic ovary syndrome. B. I. 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 simultaneously performing diagnostic curettage of the uterine cavity during wedge resection of the ovaries.

In case of stromal ovarian thecomatosis, it is necessary to take into account that it is often accompanied by symptoms of hypothalamic-pituitary syndrome. In this pathology, long-term conservative therapy is ineffective. Surgical treatment also gives a low percentage of ovarian function recovery, but significantly higher than drug therapy. It should also be noted that both in various forms of polycystic ovary syndrome and in stromal ovarian thecomatosis, treatment does not end after wedge resection. Mandatory dispensary observation is required, and 3-6 months after surgery, if it is insufficiently effective, corrective therapy is carried out, for which all the same means can be used as for self-treatment of polycystic ovary syndrome. It should be noted that, according to our data, sensitivity to clomiphene increases after surgery. This should be remembered when choosing a dose of the drug to avoid ovarian hyperstimulation. Such complex step-by-step therapy with dispensary observation allows to significantly increase the effectiveness of treatment of patients with polycystic ovary syndrome in general, including fertility.