Treatment of delayed puberty

Treatment goals for delayed puberty

• Prevention of malignancy of dysgenetic gonads located in the abdominal cavity.
• Stimulation of pubertal growth spurt in patients with growth retardation.
• Replenishment of the deficiency of female sex hormones.
• Stimulation and maintenance of the development of secondary sexual characteristics to form the female figure.
• Activation of osteosynthesis processes.
• Prevention of possible acute and chronic psychological and social problems.
• Prevention of infertility and preparation for childbirth through in vitro fertilization of donor eggs and embryo transfer.

Indications for hospitalization

Conducting treatment and diagnostic measures:

• tests with releasing hormone analogues;
• study of the circadian rhythm and nocturnal secretion of gonadotropins and growth hormone;
• tests with insulin and clonidine (clonidine) to clarify the reserves of somatotropic secretion.

Determination of the Y chromosome in the karyotype of a patient with a female phenotype is an absolute indication for bilateral removal of the gonads in order to prevent their tumor degeneration.

Non-drug treatment of delayed puberty

For girls with central and constitutional forms of delayed puberty - compliance with the work and rest regimen, correction of physical activity, maintenance of adequate nutrition and compensation for the underlying somatic disease.

Drug treatment of delayed puberty

There are no reliable data on the effectiveness of vitamin-mineral complexes and adaptogens in girls with constitutional delay of puberty. After the test with DiPr, activation of puberty was noted in such children. Girls with constitutional delay of puberty can undergo 3-4-month courses of treatment with drugs containing sex hormones in a constant sequential mode and used for hormone replacement therapy.

As non-hormonal therapy for patients with hypogonadotropic amenorrhea, a complex consisting of individually selected antihomotoxic drugs or drugs that improve the function of the central nervous system is recommended. The course of treatment should be at least 6 months. The choice of further tactics for managing the patient should be based on the dynamics of the content of gonadotropic hormones, estradiol, testosterone and data from monitoring the size of the uterus and the state of the follicular apparatus of the ovaries.

In patients with the hypergonadotropic form of delayed puberty against the background of gonadal dysgenesis, daily therapy with estrogens in gel (Divigel, Estrogel, etc.), tablet (Progynova 1-2 mg/day, Estrofem 2 mg/day, etc.) or patch (Klimara, Estroderm, etc.) or conjugated estrogens in tablets daily (Premarin at a dose of 0.625 mg/day, etc.) is indicated for the purpose of initial estrogenization of the body. The use of ethinyl estradiol in tablets daily (Microfollin 25 mcg/day) is currently limited due to the possibility of unfavorable or inadequate development of the mammary glands and uterus. Due to the high risk of malignant degeneration of the sex glands while taking estrogen drugs, hormone replacement therapy for patients with 46.XY karyotype and gonadal dysgenesis should be carried out strictly after bilateral gonadal and tubectomy.

If regular menstrual-like reactions occur, gestagens are included in the therapy complex in a cyclic mode (Duphaston (dydrogesterone) at 10-20 mg / day, Utrozhestan (progesterone) at a dose of 100-200 mg / day or medroxyprogesterone acetate at 2.5-10 mg / day from the 19th to the 28th day of estradiol intake). It is possible to prescribe estradiol both in sequential combination with progestogens (Divin, Klimonorm, Cycloproginova, Klimen) in a 21-day mode with breaks of 7 days, and in a continuous mode without breaks (Femoston 2/10). In patients over 16 years of age, it is advisable to use Divitren for the rapid appearance of secondary sexual characteristics and an increase in the uterus. To accelerate the formation of the mammary glands, it is recommended to prescribe combined oral contraceptives. After achieving the desired results in both cases, a transition to drugs used in a constant sequential mode is indicated.

In addition to hormone replacement therapy, if a decrease in bone mineral density is detected, osteogenon is prescribed at 1 tablet 3 times a day for 4-6 months annually. The drug is taken under the control of bone age until the growth zones close and under the control of densitometry of XY gonadal dysgenesis. It is advisable to conduct 6-month courses of therapy with calcium preparations: Natekal D ₃, calcium D-Nycomed, Vitrum Osteomag, calcium-Sandoz forte.

In short patients with hypo- and hypergonadotropic gonadism with growth indices below the 5th percentile, somatropin (recombinant growth hormone) is used. The drug is administered subcutaneously once daily at night. The daily dose is 0.07-0.1 IU/kg or 2-3 IU/m ², which corresponds to a weekly dose of 0.5-0.7 IU/kg or 14-20 IU/m ². As the girl grows, the dose should be regularly adjusted based on weight or body surface area. Therapy is carried out under growth monitoring every 3-6 months until the period corresponding to bone age indices of 14 years, or when the growth rate decreases to 2 cm per year or less. Girls with Turner syndrome require a higher initial dose of the drug. The most effective is the administration of 0.375 IU/kg per day, but the dose can be increased.

For short girls with Turner syndrome, oxandrolone (a non-aromatizing anabolic steroid) can be prescribed in a dose of 0.05 mg/kg per day for a course of 3-6 months in order to enhance growth, while taking growth hormone.

When choosing the type of sex steroid therapy aimed at replenishing estrogen deficiency and the dose of drugs, one should focus not on the chronological (passport) age, but on the biological age of the child. Currently, it is common to use drugs similar to natural estrogens, according to an increasing scheme, if the bone age has reached 12 years.

The initial dose of estrogens should be 1/4-1/8 of the dose used to treat adult women: estradiol in the form of a patch at 0.975 mg/week or in the form of a gel at 0.25 mg/day or conjugated estrogens at 0.3 mg/day for a course of 3-6 months. If there is no response menstrual-like bleeding during the first 6 months of taking estrogens, the initial dose of the drug is increased by 2 times and after at least 2 weeks, progesterone is additionally prescribed for 10-12 days. If bleeding occurs, it is necessary to proceed to modeling the menstrual cycle. Prescribed is estradiol in the form of a patch of 0.1 mg/week or a gel of 0.5 mg/day or conjugated estrogens at a dose of 0.625 mg/day with the addition of drugs containing progesterone (dydrogesterone at 10-20 mg/day or micronized progesterone (utrogestan) at 200-300 mg/day). Estrogens are taken daily continuously, progesterone - for 10 days every 20 days of taking estrogens. It is possible to take drugs containing an analogue of native progesterone every 2 weeks against the background of continuous use of estrogens. Over the course of 2-3 years of hormonal treatment, the dose of estrogens should be gradually increased to the standard dose, taking into account the rate of increase in body length, bone age, size of the uterus and mammary glands. The standard dose of estrogens to compensate for the deficiency of estrogenic effects, which, as a rule, does not have negative consequences, is 1.25 mg/day for conjugated estrogens, 1 mg/day for estradiol-containing gel and 3.9 mg/week for estrogen patches. Undoubtedly, drugs containing estradiol and progesterone (medroxyprogesterone, dydrogesterone) with a fixed ratio have advantages. Therapy with higher doses of estrogens leads to accelerated closure of epiphyseal growth zones and the development of mastopathy, increases the risk of endometrial cancer and breast cancer.

The main criteria for the effectiveness of the therapy are the beginning of growth and development of the mammary glands, the appearance of genital hair, an increase in linear growth and progressive differentiation of the skeleton (approaching biological age to the passport age).

Surgical treatment of delayed puberty

Surgical intervention is indicated for patients with growing cysts and tumors of the pituitary gland, hypothalamic region and the third ventricle of the brain.

Due to the increased risk of neoplastic transformation of dysgenetic gonads located in the abdominal cavity, as well as the high frequency of detection of pathology of the fallopian tubes and mesosalpinx, all patients with XY gonadal dysgenesis immediately after diagnosis require bilateral removal of the uterine appendages (along with the fallopian tubes), primarily by laparoscopic method.

Approximate periods of incapacity for work

From 10 to 30 days during examination and diagnostic procedures in a hospital setting. Within 7-10 days during surgical treatment.

Further management

All girls with constitutional delay of puberty should be included in the risk group for the development of bone mineral density deficiency and require dynamic observation until the end of puberty.

Patients with ovarian delayed puberty and hypogonadotropic hypogonadism, in the absence of effect from non-hormonal treatment, require lifelong replacement therapy with sex steroids (until the period of natural menopause) and constant dynamic monitoring. In order to avoid overdose and undesirable side effects during the first 2 years of treatment, it is advisable to conduct a control examination every 3 months. Such tactics allow to establish psychological contact with patients and promptly adjust the treatment regimen. In subsequent years, it is sufficient to conduct a control examination every 6-12 months. In the process of long-term hormonal treatment, a control examination should be carried out once a year. The minimum set of studies should include: ultrasound of the genitals, mammary and thyroid glands, colposcopy, as well as determination of the content of FSH, estradiol, progesterone in the blood plasma, according to indications TSH and thyroxine in the second phase of the simulated menstrual cycle. An estradiol level of 50-60 pmol/l is considered the minimum to ensure a response from target organs. The normal estradiol level, necessary for the functioning of the main organs of the reproductive system and maintaining normal metabolism, is within 60-180 pmol/l. At least once every 2 years, it is necessary to assess the dynamics of bone age if it lags behind the calendar age; if it is possible to study the skeletal system, the examination should be supplemented with densitometry.

Information for the patient

It is advisable to train patients in the skills of using drugs (transdermal dosage forms, growth hormone injections) and explain the need for strict control over their intake due to the risk of acyclic uterine bleeding if the treatment regimen is violated. If growth hormone therapy is necessary, patients and their parents should be trained by experienced medical personnel in the technique of administering the drug.

Patients should be informed about the need for long-term (up to 45-55 years) hormone replacement therapy to compensate for the deficiency of estrogens, which affect not only the uterus and mammary glands, but also the brain, blood vessels, heart, skin, bone tissue, etc. Against the background of hormone replacement therapy, annual monitoring of the state of hormone-dependent organs is necessary. It is advisable to keep a self-monitoring diary indicating the timing of the onset, duration and intensity of menstrual-like bleeding. Spontaneous pregnancy is impossible. But despite this, with regular intake of female sex hormones, the uterus can reach a size that allows for the transplantation of a donor egg fertilized artificially.

Interruptions in therapy of patients with hypogonadotropic and hypergonadotropic hypogonadism are not allowed. Termination of hormone replacement therapy or interruption in treatment for more than two cycles causes the development of a deep estrogen deficiency state with the appearance of vegetative reactions and metabolic disorders, hypoplasia of the mammary glands and genitals.

Forecast

The fertility prognosis in patients with constitutional delayed puberty is favorable.

In hypogonadotropic hypogonadism and ineffective therapy consisting of individually selected antihomotoxic drugs or drugs that improve CNS function, fertility can be temporarily restored by exogenous administration of LH and FSH analogues (in secondary hypogonadism) and GnRH analogues in a circulatory regimen (in tertiary hypogonadism).

In hypergonadotropic hypogonadism, only patients with adequate hormone replacement therapy by transferring a donor embryo into the uterine cavity and fully compensating for the deficiency of corpus luteum hormones can become pregnant. Stopping the medication usually results in spontaneous abortion. In 2-5% of women with Turner syndrome who had spontaneous puberty and menstruation, pregnancy is possible, but its course is often accompanied by the threat of termination at various stages of gestation. Favorable pregnancy and childbirth in patients with Turner syndrome is a rare occurrence and more often occurs when boys are born.

In patients with congenital hereditary syndromes accompanied by hypogonadotropic hypogonadism, the prognosis depends on the timeliness and effectiveness of the correction of concomitant diseases of organs and systems.

In patients with hypergonadotropic hypogonadism, with timely and adequate treatment, it is possible to realize reproductive function through in vitro fertilization of a donor egg and embryo transfer.

Patients who did not receive hormone replacement therapy during their reproductive period suffer from arterial hypertension, dyslipidemia, obesity, osteoporosis more often than the population average; they more often have psychosocial problems. This is especially true for women with Turner syndrome.

Prevention

There are no data confirming the existence of developed measures to prevent delayed puberty in girls. In central forms of the disease caused by nutritional deficiency or inadequate physical activity, it is advisable to follow a work and rest regimen against the background of rational nutrition before the onset of puberty. In families with constitutional forms of delayed puberty, observation by an endocrinologist and gynecologist is necessary from childhood. There is no prevention for gonadal and testicular dysgenesis.