RU2201225C2 - Method for treating chronic anovulation and preventing syndrome of ovarian hyperstimulation - Google Patents

Abstract

FIELD: medicine, gynecology. SUBSTANCE: one should inject metphormin by certain scheme, then clomyphen citrate should be introduced since 5th till 9th d of menstrual cycle. In case of insufficient endometrial thickness or luteal failure metphormin should be combined with application of estrogens, gestagens and LH. The suggested method provides renewal of regulatory ovulatory cycles at decreasing patient's body weight and preventing syndrome of ovarian hyperstimulation. EFFECT: higher efficiency of therapy and prophylaxis. 6 ex

Description

 The invention relates to medicine, namely to endocrinology of the female reproductive system, and relates to a method for the treatment of chronic anovulation against the background of polycystic ovary syndrome (PCOS), and can be used to achieve ovulatory cycles and pregnancy on the background of endocrine infertility, to reduce ovarian production of androgens and for the prevention of metabolic and tumor diseases associated with hyperandrogenism.

 Many years of experience using various methods of therapeutic treatment for polycystic ovary syndrome do not fully satisfy the specialists involved in this problem.

There are two main directions for improving the methods of therapeutic effect in PCOS:
1) modernization of surgical treatment methods (endoscopic surgery, electro-puncture, thermocauter, lasers);
2) clinical pharmacotherapy with attempts to induce ovulation through drugs [1].

 However, even after a successful surgical intervention, most women require subsequent drug therapy [2].

 In medical practice, the following methods of stimulating ovulation with various drugs are widely used: veroshpiron, clomiphene, combined estrogen-progestogen drugs, gonadotropic hormones and gonadoliberin agonists. The effectiveness of various ovulation induction schemes according to different authors varies from 24 to 88% with a worsening prognosis with disease progression [1].

 As a prototype, a method of using clomiphene and its analogues to stimulate ovulation, prescribed both before and after surgery on the ovaries, was used [1].

 The main disadvantages of this rather common technique are a significant risk of developing ovarian hyperstimulation syndrome and resistance to drugs of this group. Primary failure is the basis for the appointment of gonadotropins, and in the absence of a result - gonadoliberin agonists, which significantly increases the cost of treatment [1]. A positive result with monotherapy is 38%, with a combination - up to 75%. A comparative study of the results of various types of treatment for PCOS suggests that medication can only achieve a short-term effect in the form of restoration of ovulation and pregnancy. However, later polycystic ovaries remain polycystic ovaries [3]. Restoring reproductive function and treating hirsutism are not the only aspects of PCOS therapy. PCOS is known to be a significant risk factor for the subsequent development of tumor diseases of the uterus, ovaries and mammary glands, as well as metabolic disorders and related diseases (dyslipoproteinemia, atherosclerosis, type 2 diabetes mellitus) [1]. These data make it reasonable to find new ways to treat this most common disease among women of reproductive age.

 The objective of the invention is to increase the effectiveness of the treatment of PCOS and related metabolic disorders, as well as the prevention of complications of ovulation induction and the prevention of tumor diseases of the female genital area at a later age.

 This task is achieved by the use of metformin, a drug from the biguanide class, at a dose of 2 grams per day, divided into four doses until regular ovulatory monthly cycles appear.

 Justification of metformin PCOS therapy: in recent years it has been convincingly shown [4] that in the pathogenesis of PCOS, hyperinsulinemic insulin resistance is leading, causing ovarian production of androgens and reducing the level of serum sex-binding globulin, which leads to an increase in the concentration of free testosterone in plasma and the development of anovulatory ovarian dysfunction. Hyperinsulinemia stimulates the activity of ovarian cytochrome P-450, which is a key enzyme in the biosynthesis of ovarian androgens [5], correlates with ovarian volume and promotes multiple folliculogenesis [5, 6, 7] and anovulation.

 Therefore, an improvement in insulin sensitivity will lead to a decrease in circulating insulin and may allow spontaneous ovulation or make the standard ovulation inducing regimen successful. Metformin is a biguanide that increases peripheral sensitivity to insulin and inhibits hepatic glucose production, but does not cause hypoglycemia and can be prescribed to insulin-resistant but non-diabetic patients [8, 9].

The treatment algorithm we offer differs from the prototype in that:
1. Women with PCOS and anovulatory dysfunction are prescribed metformin according to a certain scheme: 1 week - 500 mg at bedtime, 2 weeks at 500 mg at bedtime and with breakfast, 3 weeks - 500 mg during breakfast, lunch and bedtime, 4 week and then 1 tablet 3 times a day with food and at bedtime.

 2. If the desired result in the form of regular ovulatory cycles is not achieved within 3-6 months of treatment with metformin, then other medications are connected depending on the identified endocrinopathy (see description of the treatment algorithm).

 The method is as follows.

1. Metformin is administered orally (with food) at a dose of 500 mg according to the following scheme:
- 1 week - 500 mg with breakfast;
- 2 weeks - 500 mg during breakfast and during lunch;
- 3 weeks - 500 mg during breakfast, lunch and dinner;
- 4 weeks onwards - 2000 mg / day (1000 mg during breakfast, 500 mg during lunch, 500 mg during dinner).

2. If ovulatory cycles were not achieved with metformin monotherapy for three months in overweight women (BMI> 25 kg / m ² ), then an anti-estrogen was added to the treatment: clomiphene citrate in a dose of 50 to 150 mg per day from the fifth to the ninth day of the menstrual cycle until a positive result is obtained in the form of pregnancy.

 3. In women who are thin or have a normal body weight after a three-month treatment with metformin, in the absence of a result on monotherapy with this drug, small doses of estrogen were connected while taking it. Indications for the appointment of estrogen were considered insufficient thickness of the endometrium (less than 4 mm), which was evaluated on 12-15 days of the previous menstrual cycle. The following estrogen preparations were used: microfollin from day 5 of the cycle to day 9 at a dose of 25 mg, from 10 to 14 days - 50 mg, from 15 to 20 days - 25 mg or premarin (conjugated estrogen) from 5 to 9 days of the cycle at a dose of 625 mg, from 9 to 14 days - 125 mg, from 15 to 20 days - 625 mg.

 4. In women with luteal insufficiency, established on the basis of graphs of basal temperature, confirmed sonographically, and on the basis of low indicators of progesterone, studied on days 21-23 during treatment with metformin, luteinizing hormone (rotten) or progestins (orgametil or Duphaston) 5 mg in two divided doses per day from 14 to 25 days of the cycle.

 5. If the menstrual cycle was not established during metformin monotherapy (against the background of amenorrhea before drug treatment), then metformin treatment was combined with combined oral estrogen-progestogen drugs. They preferred to prescribe femoden or Diana-35, as these drugs do not have androgenic properties.

 6. In the case of a combination of polycystic ovary disease with thyroid dysfunctions (diffuse colloid or nodular goiter, autoimmune thyroiditis), metformin and L-thyroxine were combined at a dose of 150-200 mcg / day.

 The advantages of this treatment algorithm are as follows.

 1. An individual approach based on the pathogenesis of ovarian dysfunction, contributing to the more rapid achievement of a positive result in the form of the desired pregnancy without surgical intervention.

 2. Elimination with the help of metformin of hyperinsulinemic insulin resistance, which is the main pathogenetic factor in the development of hyperandrogenism in women.

 3. Prevention and prevention of ovarian hyperstimulation syndrome, in the occurrence of which hyperinsulinemia plays a decisive role.

 4. With the appointment of metformin in obese women, a decrease in body weight was achieved, which is the prevention in the future of diseases associated with overweight: uterine fibroids, endometrial cancer, diabetes mellitus, atherosclerosis and other diseases of impaired metabolism.

 5. When prescribing metformin, lipid profiles improved (with a decrease in the atherogenicity coefficient) and fibrinolytic properties of the blood.

 The rationale for the treatment of chronic anovulation with metformin against the background of polycystic ovary disease.

 Polycystic ovary syndrome is the predominant endocrine dysfunction in women of reproductive age, characterized by hyperandrogenism and anovulation.

It is known (John E Nestler) that hyperinsulinemia in women with polycystic ovary syndrome produces hyperandrogenism and, possibly, ovulatory dysfunction through 2 distinct and independent mechanisms:
1) by stimulating ovarian androgenic production;
2) by directly reducing the level of serum sex-binding globulin, which leads to an increased concentration of free testosterone in plasma.

 The ratio of hyperinsulinemia and polycystic ovaries is an important clinical position because it suggests that medications that lower insulin levels by inhibiting its release from the pancreas or by improving peripheral sensitivity to it can lead to decreased circulating androgens and improved reproductive function.

 Over the past year, scientific publications have appeared on the positive effect on fertility of drugs that improve insulin sensitivity by affecting hyperinsulinemic insulin resistance and reducing the production of ovarian androgens. Based on the foregoing, we used metformin IUDs, a drug from the biguanide group, which inhibits gluconeogenesis in the liver and improves the sensitivity of peripheral tissues to insulin, thereby reducing insulin secretion in thin women and in women with excess weight and polycystic ovary syndrome (PCOS). In order to reduce the production of ovarian androgens and, therefore, restore regular ovulatory menstrual cycles in women with PCOS.

 38 women with verified PCOS with normal, reduced and overweight were randomized into the metformin group. All women had oligoamenorrhea, clinical manifestations of hyperandrogenism, normal prolactin levels, adrenal hyperplasia was excluded, and characteristic signs of PCOS were detected by ultrasound. None of the women used any medicine, none had diabetes. The study was conducted at the Arkhangelsk State Medical Academy on the basis of 1 city clinical hospital in Arkhangelsk.

 Experimental protocol.

 Women were examined on an empty stomach after a 12-hour fast, blood was taken at 8.30-9.00-10.00 and 11.00 to determine basal and stimulated levels of glucose, insulin, as well as cholesterol, triglycerides, high density lipoprotein cholesterol (HDL cholesterol) before and after an oral tolerance test glucose with a load of 75 g of glucose. After the glucose tolerance test, metformin was prescribed according to the scheme described in the claims for 12 weeks.

 Monitoring of side effects of the drug was carried out weekly, and on the twelfth to fourteenth day of the cycle, a sonographic examination of the ovaries and uterus was performed to assess the thickness of the endometrium, the presence of a leading follicle and ovulation. If pregnancy did not occur within 12 weeks, then the treatment was carried out in accordance with the algorithm described in the claims.

 The result of our study was the achievement of ovulatory cycles, the onset of spontaneous pregnancies, an improvement in the lipid profile, an improvement in glucose tolerance, and weight loss in overweight women.

Clinical examples
Example 1

Patient K., 23 years old, turned in connection with amenorrhea for 30 months and infertility. The diagnosis of polycystic ovaries was established on the basis of: hirsutism, which manifested at puberty, androgenic dermatopathy with vulgar acne, oily seborrhea, amenorrhea, increased testosterone levels of 6.9 nmol / L (normal to 5.0), a characteristic LH / FSH index of 3.32, elevated levels of LH - 12.3 mU / l and sonographic examination of the uterus and ovaries, where the ovarian-uterine index (NMR) was 3.09. The structure of the ovaries had a small cystic structure and a thickened capsule (2 mm). The volume of the right ovary was 15.20 cm ³ , the left - 10.24 cm ³ .

 When examining the thyroid gland, a diagnosis of euthyroid colloid goiter was established.

 Lipid profile: cholesterol -5.6 mmol / l, triglycerides - 2.4 mmol / l, HDL cholesterol - 1.0 mmol / l.

In addition, the patient showed impaired glucose tolerance during OGTT: 5.89-9.42-7.18 mmol / l (capillary blood) against the background of obesity (BMI - 31 kg / m ² , IT / B - 0 , 85). Immediately, metformin therapy was started according to the described protocol in combination with L-thyroxine at a dose of 150 mg / day, and after a month of treatment, menstruation first came. Subsequently, a menstrual cycle was established after 31-45 days with a tendency for endometrial hyperplasia according to sonography. Progestogens and clomiphene in an initial dose of 50 mcg per day were connected to the treatment.

 Ovulatory cycles appeared 6 months after the start of therapy. Positive dynamics was noted in the lipid profile: total cholesterol - 4.4 mmol / l, triglycerides - 2.1 mmol / l, HDL - 0.54 mmol / l. Fasting glycemia - 3.8 mmol / L. Body weight decreased by 2.5 kg. Pregnancy has not yet occurred due to the family situation. The treatment is ongoing. The state of health has improved significantly, regular ovulatory cycles remain.

 Example 2

Patient A., 23 years old. Diagnosis: polycystic ovary syndrome. Diffuse euthyroid (colloidal) goiter of 1 degree. The diagnosis was made on the basis of infertility, oligoopsomenorrhea, hyperandrogenism with diffuse hair thinning syndrome (total testosterone - 9.6 nmol / L with a norm of up to 3.5), adrogenic dermopathy (acne, oily seborrhea, hirsutism), a characteristic LH / FSH ratio = 1 , 6, where the level of LH is 7.1 mU / l, the normal level of prolactin is 5.8 ng / ml. Ovarian sonography: the volume of the left ovary is 10.3 cm ³ and the volume of the right ovary is 18.19 cm ³ with hypoechoic formations in the structure, the absence of a leading follicle. Plots of basal temperature are monophasic, anovulatory type. NMI amounted to 3.96. Lipid profile: cholesterol - 3.21 mmol / l, triglycerides - 1.79 mmol / l, HDL cholesterol - 0.61 mmol / l. Fasting glycemia - 4.2 mmol / L. Thyroid gland: volume 6.54 cm ³ , hypoechoic with cystic inclusions of small sizes 0.5x0.2 and 0.3x0.2 cm on the right and left. Cytology: thick colloid, single thyocytes characteristic of colloid goiter. Antibodies to peroxidase: 4.49 U / ml (normal to 20), TSH - 3.2 mU / L, T4 - 117.5 nmol / L, T3 - 2.1 nmol / L.

 Treatment: metformin for three months according to the described scheme with subsequent connection of microfollin according to the scheme.

 Treatment result: manifestations of androgenic dermopathy decreased, a regular ovulatory cycle lasting 32 days was established.

 Example 3

 Patient R., 22 years old. Diagnosis: polycystic ovary syndrome, secondary amenorrhea. Dyshormonal mastopathy.

The diagnosis was made on the basis of clinical and sonographic symptoms: obesity with BMI - 25.52 kg / m ² , IT / B - 0.76, hirsutism - 9 points, vulgar acne, LH / FSH ratio - 6.28, LH - 20, 1 mU / l, FSH - 3.2 mU / l, prolactin - 20.0 ng / ml, NMR - 3.62. The ovaries are enlarged, cystically altered. Lipid profile: cholesterol - 4.51 mmol / l, triglycerides - 1.10 mmol / l. Fasting glucose - 5.4 mmol / L.

 The patient received metformin treatment for 3 months, then femoden was connected for 3 months, and a month after the cancellation of femoden, pregnancy began, which is currently progressing. During the treatment, she lost 5 kg.

 Example 4

 Patient X., 35 years old. Diagnosis: polycystic ovary syndrome. Infertility I. It had regular but anovulatory cycles with luteal phase insufficiency (progesterone in phase II - 14.82 nmol / l), a monophasic curve according to the basal temperature graphs, and there was no leading follicle during sonographic examination. At the age of 20, she underwent a wedge-shaped ovarian resection; pregnancy did not occur after surgery. After the operation, she underwent several courses of therapy with clomiphene in combination with a CG poplite for ovulation, but there was no effect from therapy.

The patient is suffering from abdominal obesity (BMI - 25.7 kg / cm ² , IT / B - 0.90), arterial hypertension, hyperlipidemia, she had a positive test for microalbuminuria.

 She received treatment at a dose of 2000 mg / day for four months, against the background of which ovulatory cycles first appeared (the presence of a leading follicle was regularly monitored sonographically).

 Example 5

Patient V., 24 years old. Diagnosis: polycystic ovary syndrome. Anovulation, infertility. Obesity of the III degree (BMI - 36.57 kg / m ² ). Diffuse-nodal euthyroid (colloidal) goiter.

 The diagnosis was made on the basis of the clinical manifestations of PCOS: hirsutism, oligomenorrhea, monophasic plots of basal temperature, overweight, arterial hypertension, small follicular, polycystic ovarian structure during sonographic examination, infertility for 3 years.

 Treatment: metformin at a dose of 2000 mg / day for 2 months, spontaneous pregnancy occurred at 3 months of treatment, which is currently successfully progressing.

 Example 6

 Patient D., 21 years old. Barren marriage for 1 year. A diagnosis of polycystic ovary syndrome was established during laparoscopic examination with ovarian resection. After the operation, anovulatory cycles were preserved.

 Metformin treatment according to the specified scheme with connection in 3 months "Diane-35" for 4 months. Then, against the background of the cancellation of "Diane-35," one course of stimulation of ovulation with clomiphene at a dose of 50 mg. A pregnancy has begun, which is currently progressing.

 Thus, from the proposed examples, it follows that metformin leads to the resumption of regular ovulatory cycles in all patients with PCOS and timely therapy that corrects concomitant endocrine dysfunctions or stimulates ovulation leads to the desired pregnancy. In addition to this main effect, all women achieved positive dynamics in the lipid profile (lowering cholesterol, increasing HDL cholesterol), improving carbohydrate tolerance, eliminating algodismenorea and mastalgia or mastopathy. In overweight patients, body weight decreased and waist volume decreased, and with initial normal or reduced weight, body weight remained unchanged. Appetite changed selectively: the need for fats and sweet foods decreased, there was no need to eat in the evening. The proposed method avoided hyperstimulated ovary syndrome and surgical intervention (except for those women who were included in the study after unsuccessful surgical interventions preceding treatment with metformin).

Literature
1. Vikhlyaeva E. M., "Guide to endocrine gynecology", M., 1997, p. 360-395.

 2. Yeltsov-Strelkov V.I., Orlova V.G., Grozovskaya L.V. "The effectiveness of various methods of surgical treatment of patients with polycystic ovary", Obstetrics and gynecology, 1984, 11, 44-48.

 3. Burger C., Korsen T., Hompes P. et al. "Ovulation induction with pulsate luteinsing hormone - releasing hormone in women with clomiphene resistant polycystic ovary - like disease", Fertil. Steril. - 1986, Vol. 46, 11, 1045-1054.

 4. John E. Nestler, MD. "Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implication", In: Seminars in reproductive endocrinology, pp. 111-122, Copyright 1997 by Thieme Medical Publishers Inc.

 5. Ehrmann D.A., Rosenfield R. L., Barness R. B., Brigell D. F., Sheikh Z. "Detection of functional ovarian hyperandrogenism in women with androgen excess", N. Engl. J. Med. 327: 157-162, 1992.

 6. Nobels F., Dewailly D. "Puberty and polycystic ovarian syndrome: The insulin / insulin-like growth factor I hypothesis", Fertil. Steril, 58: 655-666, 1992.

 7. Filicori M, Flamigni C., Cognigni G., Dellai P., Michelacei L., Arnone R., "Increased insulin secretion in patients with multifollicular and polycystic ovaries and its impact on ovulation induction", Fertil. Steril, 62: 279-285, 1994.

 8. DeFronzo R.A., Barsilai N., Simonson D.C. "Mechanism of metformin action in obese and lean noninsulin dependent diabetic subjects", J. Clin. Endocrinol. Metab. 73: 1294-1301, 1991.

 9. Velazques E.M., Mendosa S., Hamer T., Sosa F., Glueck C.J. "Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulinresistance, hyperandrogenia and systolic blood pressure while facilitating normal menses and pregnancy", Metabolism, 43: 647-654, 1994.

Claims (1)

 A method for the treatment of chronic anovulation and prevention of ovarian hyperstimulation syndrome in women with polycystic ovary syndrome, characterized in that metformin is administered at a dose of 500 mg before bedtime and the dose is increased 500 mg to 2000 mg per day with four times and continue treatment for 3-6 months, then enter clomiphene citrate at a dose of 50-150 mg per day from 5 to 9 days of the menstrual cycle, and in case of insufficient thickness of the endometrium or with luteal insufficiency the administration of metformin is combined with the administration of estrogens, progestogens and luteinizing hormone.