RU2422824C1 - Method of choosing therapeutic approach in menstrual disorders in adolescent girls with overweight - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: in adolescent female patients with overweight suffering menstrual disorders of oligomenorrhea or amenorrhea type are examined for a body weight index (BWI) and blood serum leptin level measured by enzyme immunoassay. And if the BWI of the patient exceeds 25.0 kg/m², and the leptin level is less than 32.52 ng/ml, diet therapy and graduated physical activity are prescribed. The leptin level 32.52 ng/ml and higher in the patient requires additional glucose tolerance test to a common technique to detect insulin resistance. If observing insulin resistance, the complex treatment includes the preparations to provide higher peripheral tissue sensitivity (sensitisers) to insulin. The absence of insulin resistance enables to prescribe the therapy of combined oral contraceptives with drospirenone.

EFFECT: method allows prescribing well-timed adequate therapy for treating said disease and evaluating the efficacy of the performed therapy.

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Description

The invention relates to medicine, namely to gynecology, and will find use in solving the issue of choosing a method for restoring menstrual function in adolescent girls with oligomenorrhea and overweight.

It is known that obesity has an adverse effect on the reproductive function of women (Serov V.N., Kan N.I., 2004). Among women with a normal menstrual cycle, the incidence of obesity is 13%, and it is known that in 96% of them, obesity began in the post-puberty period.

Timely correction of body weight leads to a normalization of the cycle, in many patients even without the use of any additional therapy, and to the restoration of fertility. To restore regular menstruation, it is enough to reduce body weight by 10-15%, but it is far from always possible to achieve such an effect with the help of a diet.

One of the common mistakes in the management of this patient population is that before the appointment of treatment for obesity, ovarian function is stimulated. With prolonged stimulation of ovulation without weight loss, premature ovarian exhaustion syndrome may develop (Marine Norman et al., 1991). These results indicate the need to begin treatment of patients with weight loss.

In adolescent girls with menstrual rhythm disorder and obesity, combined oral contraceptives (COCs) are traditionally used to regulate the menstrual cycle and reduce the effects of relative hyperestrogenia and hyperandrogenism. Since COCs may have a negative effect on insulin sensitivity, there are theoretical concerns about their use in patients with proven insulin resistance.

Methods for treating obesity with orlistat and sibutramine are described (Zhi J, Melia AT, Guerciolini R et al. The effect of orlistat on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. J Clin Pharmacol. 1996; 36: 659-66; Colman E, Fossler M. Reduction in blood cyclosporine concentrations by orlistat. N Engl J Med. 2000; 342: 1141-2; Melia AT, Mulligan TE, Zhi J. The effect of orlistat on the pharmacokinetics of phenytoin in healthy volunteers. J Clin Pharmacol. 1996 ; 36: 654-8; Hauptman J, Lucas C, Boldrin MN et al. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med. 2000; 9: 160-7).

Metformin is used to increase the sensitivity of tissues to insulin (D.E. Shilin. Polycystic ovary syndrome: the role of insulin resistance and its correction / - Petrozavodsk: IntelTech, 2004. - 52 p .; Shubina A.T., Demidova I.Yu., Chernova N.A., Karpov Yu.A. Metabolic syndrome: the possibilities of using metformin / // Russian Medical Journal. - 2001. - T.9, No. 2. - P.77-99; Manukhin I.B. Androgens and insulin resistance / I. B. Manukhin, M. A. Gevorgyan, N. B. Chagai // Problems of reproduction. - 2005. - No. 2. - P.27-31).

Suppress insulin synthesis by diazoxide and somatostatin (Avenell A. What interventions should we add to weight reducing diets in adults with obesity? A systematic review of randomized controlled trials of adding drug therapy, exercise, behavior therapy or combinations of these interventions / A. Avenell , TJ Brown, M.A. McGee et al. // J. Hum. Nutr. Dietet. - 2004 .-- Vol.17. - P.293-316).

The results of the study of Miller KK, Parulekar MS, Schoenfeld E. at al. (Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. // J Clin Endocrinol Metab. 1998 Jul; 83 (7): 2309-12), who studied the role of leptin as a regulator of reproductive function. The authors compared leptin levels in women with hypothalamic amenorrhea and in normally menstruating women who have equal (normal) body mass index values, calories consumed with food, and the same age. It was found that leptin levels were significantly lower in patients with hypothalamic amenorrhea compared with the control group. This method is chosen by us for the prototype of the claimed invention.

Nevertheless, there are no clear recommendations for the treatment of adolescent girls depending on the severity of neuro-endocrine-metabolic disorders in the modern medical literature. Thus, the lack of a single point of view on the feasibility and timing of prescribing hormonal contraceptives to overweight patients creates the need to develop a method for choosing tactics for restoring menstrual function in this category of patients.

This indicates the need for a differentiated approach when choosing methods for correcting body weight and treating ovarian dysfunction in adolescent girls, which will help restore normal reproductive function and prevent possible long-term complications.

To select a treatment tactic, it is first necessary to develop clear differential diagnostic criteria by which to predict the further course of the disease - that is, to determine whether a spontaneous restoration of the menstrual cycle is possible only against the background of diet therapy and rational physical activity or if drug therapy is necessary.

The claimed invention allows to solve this problem.

The objective of the invention is the development of an accurate differential approach and determine further tactics for treating menstrual dysfunction in patients in puberty with overweight.

The problem is solved in that in adolescent girls with excess body weight (BMI exceeding 25.0 kg / m ² ) suffering from menstrual dysfunction by the type of oligomenorrhea or amenorrhea in the blood serum by ELISA, the level of leptin is determined, and with the value of this indicator less than 32.52 ng / ml, therapeutic tactics is to prescribe diet therapy and dosed physical activity. If a patient (with a BMI exceeding 25.0 kg / m ² ) in the puberty period of her life, suffering from menstrual dysfunction such as oligomenorrhea or amenorrhea, has a leptin level of 32.52 ng / ml or higher, it is necessary to additionally conduct a glucose tolerance test according to the generally accepted a technique for establishing insulin resistance. In the presence of insulin resistance - in the tactics of complex treatment of the patient include drugs that increase the sensitivity of peripheral tissues (sensitizers) to insulin. In the absence of insulin resistance, they include therapy with combined oral contraceptives with drospirenone.

We found that with obesity and a regular menstrual cycle, the level of leptin corresponds to values not exceeding 32.52 ng / ml. If the menstrual cycle is disturbed due to obesity, this indicator exceeds the established diagnostic threshold - the “critical” level.

In order to develop differentiated treatment regimens for adolescent girls with obesity, we have developed an algorithm to select the optimal tactics for managing these patients.

The diagnostic accuracy of this classification model is 70%, sensitivity - 83.3%, specificity - 60%.

The technical result achieved by this invention in clinical practice is that the use of this technique will help:

1) timely predict the further course of the disease;

2) to objectify the assessment of the effectiveness of treatment aimed at restoring menstrual function.

With ongoing amenorrhea and leptin levels of 32.52 ng / ml and higher, even despite the normalization of weight achieved, the patient needs additional research - conducting a glucose tolerance test according to the generally accepted method for establishing insulin resistance.

In the presence of insulin resistance, the patient is treated with drugs that increase the sensitivity of peripheral tissues (sensitizers) to insulin.

In the absence of insulin resistance, the question of the need for prescribing therapy with combined oral contraceptives with drospirenone should be raised in a timely manner. The need and timeliness of starting hormone therapy is due to progressive hyperplastic processes in the endometrium against the background of absolute or relative hyperestrogenism, which can lead to irreversibility of damage to the reproductive axis.

The identification and isolation at the end of 1994 of the obesity gene - ob - and its leptin product made us take a fresh look at the mechanisms that control weight. Recent studies (Miller K.K., Parulekar M.S., 1998) revealed a correlation between the level of plasma leptin and disorders in the reproductive system. The existence of a “critical level” of leptin is discussed, at which the formation of the ovarian-menstrual cycle is possible (Laughlin G.A., Yen S.S.C., 1997). It is possible that leptin acts as a metabolic signal that provides a link between body composition and reproductive function and is one of the factors supporting the circhoral rhythm of GRH secretion (Thong F.S., Graham T.E., 1999).

In 1996, it was first suggested that the physiological role of leptin during fasting is the regulation of the neuroendocrine system. Initiation of puberty in animals and humans is associated with an increase in the level of leptin, and its normal concentration in the blood is necessary to establish ovulatory menstrual cycles that ensure the realization of reproductive function. Moreover, circadian changes in leptin parameters are associated with fluctuations in the levels of LH and estradiol in women.

According to some data, leptin may have a direct effect on ovarian steroidogenesis, but the specific role of intraovarial leptin in the physiology and pathology of the human reproductive system requires further scientific explanation (Mantzoroz C.S., 2000). Reduced leptin levels are associated with a drop in LH concentrations and amenorrhea in athletes and patients with anorexia nervosa. It is the low level of leptin that underlies the metabolic and neuroendocrine changes characteristic of anorexia nervosa and therapeutic fasting (Ametov A.S., Demidova T.Yu., Tselikovskaya A.L., 2001). The study of leptin in patients with anorexia nervosa (BMI = 15.4) compared with women without eating disorders with a normal body mass index (20.3) revealed a significant decrease in patients with anorexia nervosa compared with healthy women (3, 61 and 9.37 ng / ml) (Halusik M., Papezova M., Nedvidkova J. et al., 1999). It was noted that against the background of restoration of body weight, there is an increase in the concentration of both luteinizing hormone and leptin (Barash I.A., Cheung C.C., Weigle D.S. et al., 1996).

However, these data primarily demonstrate the relationship of hypoleptinemia with hypothalamic dysfunction and amenorrhea, as well as the lack of correlation of leptin levels with body weight, which allows us to consider the mechanism and reproductive effects of low leptin levels as yet unknown.

The study of leptin levels was carried out by enzyme immunoassay using ELISA test systems (USA). The statistical substantiation of differences between the selected groups of patients was carried out using the Mann-Whitney U-test with a maximum acceptable level of probability of error of the first kind p = 0.05. The calculations were carried out in the environment of the Statistica 6.0 application software package.

The study of this indicator in the main group made it possible to establish fundamental differences with the levels of control and the comparison group. So, leptin indices in the main group before treatment were 1.35 times higher than in the comparison group (p = 0.000759) and 2.91 times higher than in the control group (p = 0.000001). When comparing the leptin indices of healthy teenage girls and obese patients, but without menstrual dysfunction, it was found that the control indices were 2.16 times lower than in the comparison group (p = 0.005349).

Based on this study, we made the following conclusion: with excess body weight in the puberty period of life, patients have hyperleptinemia and leptin resistance. Depending on the severity of the identified dysmetabolic disorders, it is necessary, firstly, to determine the prognosis of the further course of the disease, and secondly, to determine the further treatment tactics.

With leptin levels below 32.52 ng / ml, overweight and menstrual dysfunction, the patient does not need drug therapy. The prognosis of restoration of menstrual function is considered favorable, and therapeutic tactics may be limited by diet therapy and physical activity.

At a leptin level of 32.52 ng / ml and above, overweight and menstrual dysfunction, the patient needs additional research - conducting a glucose tolerance test according to the generally accepted method for establishing insulin resistance. In the presence of insulin resistance, the patient is treated with drugs that increase the sensitivity of peripheral tissues (sensitizers) to insulin. In the absence of insulin resistance, therapy is prescribed with combined oral contraceptives with drospirenone.

Description of the method and examples of clinical performance.

In adolescent girls with overweight (BMI = 25.0-29.0 kg / m ² ) and menstrual rhythm disorder according to the type of secondary amenorrhea (N91.1), secondary oligomenorrhea (N91.4) determine the concentration serum leptin.

Body mass index (kg / m ² ) - the ratio of body weight, expressed in kilograms to square of growth, expressed in meters: BMI = Body weight (kg) / Height (m ² ).

- Normally BMI from 18.5 to 25 kg / m ²

- BMI from 25.0 to 29.9 - Overweight

Determination of leptin is carried out by enzyme immunoassay using test systems Human leptin ELISA (DSL-10-23100i) USA.

If a patient in the puberty period of life with a BMI exceeding 25.0 kg / m ² , suffering from menstrual dysfunction such as oligomenorrhea or amenorrhea, has leptin levels below 32.52 ng / ml, she does not need further study of carbohydrate metabolism and drug therapy . The choice of therapeutic tactics may be limited by diet therapy and physical activity. The prognosis for the restoration of menstrual function is favorable.

If a patient in the puberty period of life with a BMI exceeding 25.0 kg / m ² , suffering from menstrual dysfunction such as oligomenorrhea or amenorrhea, has a leptin level of 32.52 ng / ml or higher, an additional glucose tolerance test should be performed according to the generally accepted method to establish insulin resistance. To determine glucose in the blood, the glucose oxidant method is used using the Olveks Diagnostic kit of reagents (St. Petersburg). The level of immunoreactive plasma insulin is determined on an empty stomach by the radioimmunological method using commercial kits from Cisbio international (France). Standards and units of measurement - 3-20 mkU / ml.

In the presence of insulin resistance - the patient’s treatment tactics include drugs that increase the sensitivity of peripheral tissues (sensitizers) to insulin - metformin (glucophage, siofor). Metformin is a sensitizer to insulin. Under its action, the affinity of insulin receptors increases, their conformation changes, receptor and postreceptor routes of transmission of the insulin signal are stimulated, kinase activity and processes of insulin receptor phosphorylation are enhanced.

In the absence of insulin resistance - prescribe therapy with combined oral contraceptives with drospirenone - the drug Yarina. It contains 30 μg of ethinyl estradiol and 3 mg of drospirenone, which determines its antimineralocorticoid and antiandrogenic effect. Like progesterone, drospirenone does not have androgenic, estrogenic, and antiglucocorticoid activity. The antiandrogenic effect of Yarina is due to the ability of drospirenone to interact with androgen receptors as a competitive inhibition. In addition, drospirenone does not interfere with the estrogen-dependent increase in the level of sex steroid-binding globulin and does not interact with this protein. The drug was taken in contraception mode - from 5 to 25 days of the menstrual cycle.

Example No. 1.

Patient St., 16 years old. Was admitted to the hospital with complaints of delayed menstruation for 2-6 months over the past 2 years. Violation of the menstrual cycle began after an increase in weight of 8 kg for 3 months at the age of 14. Before the disease, weighed 55 kg with a height of 160 cm (BMI = 21.5 kg / m ² ), weight during initial treatment - 70 kg with a height of 162 cm (BMI = 26.7 kg / m ² ), the weight in the menarch was 50, 5 kg with a growth of 158 cm (BMI = 20.2 kg / m ² ). The girl was diagnosed with secondary amenorrhea. Overweight.

To determine the further tactics of treating the disease and effective recovery of the menstrual cycle, the level of leptin was determined, which amounted to 31.90 ng / ml, which indicated a favorable prognosis for the restoration of the menstrual cycle. The treatment of the patient was carried out inpatiently (during the examination period) and, then, on an outpatient basis on the basis of a multidisciplinary approach, with the mandatory participation of a gynecologist and endocrinologist. The patient was assigned a nutritional system with a reduced calorie content (-500 kcal / day from the physiological norm, but not lower than 1000 kcal / day) and a fat restriction of up to 25-30% of the total calorie intake. The goal of treatment - the correction of metabolic, endocrine and somatic disorders under the control of clinical and biochemical monitoring - was achieved after 3 months.

Second visit. As a result of treatment, a decrease in body weight of 6 kg was achieved, the weight at present is 64 kg (BMI = 24.4 kg / m ² ). After 2 months from the start of treatment, the patient underwent 1 menstruation. The level of leptin was determined - 18.5 ng / ml, which is normal.

Thus, after 3 months from the first visit and the start of treatment, the level of leptin was 18.5 ng / ml, which was below the diagnostic threshold - 32.52 ng / ml. These results indicated the effectiveness of treatment and a favorable prognosis of the restoration of menstrual function.

Example No. 2.

Patient N, 17 years old. Was admitted to the hospital with complaints of a lack of menstruation in the last 6 months, delayed menstruation up to 6-8 months in the last 3 years, and overweight. Menstrual irregularities began with the menarche at the age of 12. Overweight in a patient from 3 years of age.

Objective examination: height 170 cm, weight 81 kg, BMI = 28 kg / m ² .

A study of the level of leptin, which was 42 ng / ml. Additionally, an oral glucose tolerance test was performed with a load of 75 g of glucose. Test results: IRI values at 120 minutes - 112 mcd / ml, Caro index - 0.2 mol / l / mced / ml and IRI / glucose ratio - 4.8 mcd / ml / mol / l. Insulin resistance has been ascertained.

Diagnosis: secondary amenorrhea. Overweight. Insulin resistance.

The treatment tactics, including complex therapy, a diet with a reduced calorie content (-500 kcal / day from the physiological norm, but not lower than 1000 kcal / day) and a fat restriction of up to 25-30% of the total calorie intake, were selected. Dosed physical activity. In connection with the revealed insulin resistance, metformin was prescribed in a daily dose of 1500 mg, divided into 3 doses.

Second visit. As a result of a 3-month treatment, a decrease in body weight of 5.5 kg was achieved. Weight - 75.5 kg, height - 170 cm, BMI = 26.12 kg / m ² . The level of leptin was studied, equal to 34 ng / ml. Given the excess of the diagnostic threshold of 32.52 ng / ml with this indicator, a repeated 3-month course of treatment with metformin and a rational diet therapy with dosed physical activity were prescribed.

Third visit. After 3 months, an anthropometric study was again performed: weight 72 kg, height 170 cm, BMI = 24.9 kg / m ² . Leptin level = 30.4 ng / ml. The menstrual cycle is regular. Recommended: adherence to a low-calorie diet, daily calorie intake should not exceed 1500 kcal, physical activity.

Fourth visit. After 3 months: weight 71 kg, height 170 cm, BMI = 24.6 kg / m ² . Leptin level = 29.6 ng / ml. The menstrual cycle is regular.

Example No. 3.

Patient F-ko, 18 years old. Was admitted to the hospital with complaints of a lack of menstruation in the last 3 months, delayed menstruation up to 6-8 months with menarche and overweight. Menstrual irregularities began with the menarche at the age of 11. Overweight in a patient from 11 years old.

Objective examination: height 159 cm, weight 69 kg, BMI = 27.6 kg / m ² , hirsutism, hypertrichosis.

A study of the level of leptin, which was 32.52 ng / ml. An oral glucose tolerance test was performed with a load of 75 g of glucose. Test results: IRI values at 120 minutes - 24 mcd / ml, Caro index - 0.64 mmol / l / mced / ml and IRI / glucose ratio - 1.5 mcd / ml / mol / l. A lack of insulin resistance has been reported.

Diagnosis: Amenorrhea secondary. Overweight.

Considering that the level of leptin is equal to the level of the diagnostic threshold, there is no insulin resistance, the use of COCs with drospirenone against the background of diet therapy and physiotherapy exercises was chosen as a therapeutic tactic. A 6-month course of taking Yarina in contraception was prescribed, along with a low-calorie diet (-500 kcal / day from the physiological norm, but not lower than 1000 kcal / day) and a fat restriction of up to 25-30% of the total calorie intake. Dosed physical activity. Return visit after 3 months.

Second visit. As a result of a 3-month treatment, a decrease in body weight of 7 kg was achieved. Weight - 62 kg, height - 159 cm, BMI = 24.8 kg / m. The level of leptin was studied, equal to 30 ng / ml. The menstrual cycle is regular.

Third visit. After 3 months, the results of anthropometric studies are the same, the menstrual cycle is regular, leptin level = 25.4 ng / ml. The forecast is favorable.

Thus, the claimed method allows us, from the standpoint of evidence-based medicine, to select an adequate treatment tactic and objectify the evaluation of the effectiveness of treatment aimed at restoring menstrual function, in order to timely predict the further course of the disease, which will help prevent the development of hyperplastic processes in the endometrium against the background of absolute or relative hyperestrogenia and the development of type 2 diabetes.

The method has a sensitivity of 83.3%, specificity of 60%, accuracy of 70%.

The method can be widely used in gynecological and endocrinological hospitals, as well as in clinics at the gynecological and endocrinological receptions.

Claims (1)

A method for choosing the tactics of treating menstrual irregularities in overweight teenage girls by determining body mass index and blood leptin level, characterized in that in patients with puberty who are overweight and suffering from menstrual dysfunction like oligomenorrhea or amenorrhea , calculate the body mass index (BMI) and determine by serum ELISA the level of leptin and, if the patient's BMI exceeds 25.0 kg / m ² and the level of leptin is less than 32.52 ng / ml, diet therapy and dosages are prescribed These physical activities, if the patient has a leptin level of 32.52 ng / ml and higher, an additional glucose tolerance test is carried out according to the standard method and insulin resistance is detected: in the presence of insulin resistance, complex treatment includes drugs that increase the sensitivity of peripheral tissues (sensitizers) to insulin; in the absence of insulin resistance, therapy is prescribed with combined oral contraceptives with drospirenone.