Treatment of disorders of sexual development

Treatment of congenital pathology of sexual development consists of several aspects. The main issue is to establish the civil sex of the patient, adequate to his biological and functional data, taking into account the prognosis of the possibility of sexual life.

In cases of underdeveloped genitalia corresponding to a certain sex, absence or surgical removal of gonads, as well as growth disorders, it is necessary to carry out hormonal correction of development, forming a phenotype approaching the norm and ensuring a normal level of sex hormones.

Surgical sex reassignment involves the formation of external genitalia depending on the chosen sex (feminizing or masculinizing reconstruction), as well as the decision on the fate of the gonads (their removal, removal from the abdominal cavity, or lowering the testicles into the scrotum). When choosing the male sex for patients with testicular dysgenesis, from our point of view, removal of the rudimentary uterus is not necessary, since its presence does not cause any complications in the future. Some patients with incomplete masculinization syndrome and testicular feminization require the creation of an artificial vagina.

The choice of gender, as in all cases of hermaphroditism, depends on the degree of masculinization of the external genitalia and the androgen-producing capacity of the testicles. Due to the decrease in tissue sensitivity to androgens, androgen replacement therapy does not always give the desired effect. Surgical correction in the male direction is facilitated by the fact that the testicles are most often located extra-abdominally, so there is no need for laparotomy. A biopsy of both testicles is necessary not only for oncological indications, but also to predict their functional capabilities.

Surgical correction in the female direction is complicated by the functional inferiority of the vagina: in addition to feminizing plastic surgery of the external genitalia and removal of the testicles, in most cases it is necessary to perform an operation to create an artificial vagina. The works of recent years have shown the justification of one-stage corrective surgical measures in childhood. Using the method of sigmoid colpopoiesis, they proved its effectiveness not only from the standpoint of functional capabilities for sexual life in the future, but also the enormous deontological significance of complete early correction.

The tactics regarding testicles before puberty are uniform: if there are no tumor changes, they are ventrofixed. During puberty, the testicles may exhibit undesirable androgenic activity, causing a coarsening of the voice, hirsutism. Then they are removed from under the abdominal skin, where they were fixed.

Hormonal correction when choosing the female direction of development is substitutional, but differs from that in congenital pathology of sexual development with preserved derivatives of Müllerian derivatives. Due to the absence of the uterus, the menstrual function is irreplaceable, so there is no need for cyclic administration of female sex hormones; they are given constantly, daily for the entire period corresponding to the fertile age. This achieves the development of female secondary sexual characteristics, complementing surgical rehabilitation.

Hormonal therapy for female patients

In case of agenesis or in cases when the female sex is chosen in testicular forms of hermaphroditism, and the testicles have to be removed for oncological indications or to avoid unwanted androgenization, there is a need for therapy with female sex hormones. This treatment is of a substitution nature (it compensates for the lack of endogenous estrogens). Therefore, from puberty, treatment continues throughout the entire period corresponding to the reproductive age. The goal of therapy with female sex hormones is to promote the correct formation of the female phenotype, the development of female secondary sexual characteristics and genitals, and to prevent the manifestation of castration syndrome. In patients with the absence of gonads, the content of gonadotropins increases sharply from puberty, reflecting the state of overstrain of the hypothalamic-pituitary system. Evidence of the adequacy of replacement therapy with female sex hormones is a decrease in the level of gonadotropins in the blood to normal.

In patients admitted for observation at prepubertal age, estrogen treatment is recommended to begin no earlier than the period corresponding to physiological puberty, taking into account the child's growth and the degree of lag of bone age from the actual one. In case of tall stature and a sharp lag of bone age (which is more often observed in "pure" gonadal agenesis and the eunuchoid form of incomplete masculinization syndrome), estrogen therapy should be started already at 11-12 years. This promotes faster maturation of the skeleton and prevents the development of subgigantism and eunuchoid body proportions. In case of short stature ("turneroid" forms) and a slight lag of bone age from the actual one, treatment should preferably be started at 14-16 years, so that the closure of the "growth zones" occurs as late as possible.

Since the treatment is long-term, it is preferable to prescribe oral medications. Only in cases where their use is undesirable for some reason (poor tolerance, low efficiency), it is necessary to resort to parenteral administration of prolonged-release estrogenic drugs (estradiol dipropionate, estradiol benzoate, etc.). Usually, during estrogen therapy, they try to imitate a gradual increase in their level during puberty. Treatment can be started either immediately according to a cyclic (intermittent) scheme, or initially continuously, until induced menstruation occurs. We prefer the continuous type of starting estrogen therapy, since menstrual-like bleeding usually appears against this background, which, in our opinion, reflects the patient's own hypothalamic cycles. "Adapting" to the identified cycles, further treatment can be carried out according to a cyclic scheme from the 5th to the 26th cycle. Naturally, the appearance of induced menstruation is possible only in patients with preserved Müllerian derivatives, i.e. with gonadal agenesis and testicular dysgenesis syndrome. In other patients, there is no need to switch to this therapy regimen.

Biohormonal treatment with estrogens and gestagens is carried out later, when the development of estrogen-dependent target organs (mammary glands, external and internal genitalia) becomes sufficient and natural two-phase cycles are imitated. Considering the psyche of patients who are forced to undergo treatment for many years, the schemes should be simplified as much as possible. The best effect is achieved by replacement therapy with biohormonal estrogen-gestagen drugs, widely used in healthy women for contraception (infecundin, bisecurin, non-ovlon, etc.). The estrogen content in them is sufficient to cause induced menstruation and further development of secondary sexual characteristics. The gestagen component prevents pathological manifestations of relative hyperestrogenism (hyperplastic processes in the endometrium and mammary glands).

We observed a good effect from the combination of synthetic estrogens with the introduction of a 12.5% solution of oxyprogesterone capronate, 1 ml intramuscularly on the 17th day of the induced cycle. We consider interruptions in replacement therapy with female sex hormones in patients with gonadal agenesis and after castration to be categorically contraindicated: withdrawal of hormone therapy immediately leads to an increase in the gonadotropic activity of the pituitary gland according to the type of postcastration syndrome and contributes to the development of endocrine-exchange and vascular disorders characteristic of it. A high level of gonadotropins can stimulate the occurrence of metastases of gonadal tumors. At the same time, estrogen replacement therapy in gonadal agenesis and castration, in contrast to the use of these hormones with preserved ovaries (for example, as contraceptives or in climacteric disorders), does not lead to the risk of developing endometrial cancer or breast cancer, since the dosages of estrogen drugs are not combined with endogenous estrogens and do not provide a high saturation of the body with these hormones.

In case of insufficient development of pubic hair, additional administration of androgens, such as methyltestosterone (5-10 mg sublingually for 3-4 months from the 5th to the 26th cycle imitated by estrogen preparations) is justified in some cases. With preserved sensitivity to androgens, satisfactory sexual hair development develops during this period, although the development of the mammary glands may be inhibited. Our observations of this group have lasted for about 30 years. It includes several hundred patients with various forms of prepubertal absence of ovaries and in postcastration states.

The obtained results give grounds to speak about high efficiency of the principle of substitution therapy with preparations of female sex hormones chosen by us. As a rule, complete feminization of the phenotype is achieved: vegetative disorders characteristic of castration syndrome are eliminated; the inferiority complex caused by the absence of sexual development disappears; the patient can start a family.

Contraindications to replacement therapy with such drugs in this group of patients are very limited: individual intolerance and severe liver disease.

After removal of the gonads due to gonocytoma, dysgerminoma, there are no contraindications to postoperative replacement therapy with female sex hormones. On the contrary, these conditions are the basis for enhanced treatment, since gonadal tumors are hormone-dependent, and increased gonadotropic activity after castration is undesirable.

Complications during hormone replacement therapy were limited to individual intolerance to the drug, requiring its replacement or transition to parenteral administration of estrogens. Rare phenomena of relative hyperestrogenization (mastopathy, prolonged menorrhagia) were observed. As a rule, the addition of gestagens eliminated these phenomena.

Hormonal therapy of patients with male civil sex. If patients with various forms of hermaphroditism choose male sex, and the development of male secondary sexual characteristics is slow or insufficient, there is a lag in the "bone age" from the actual one, there is a risk of developing eunuchoidism and disorders such as castration syndrome, there are complaints of sexual weakness, then it is necessary to resort to treatment with androgenic drugs.

Unlike patients with gonadal dysgenesis with a female phenotype, who require constant estrogen replacement therapy due to the absence of gonads, the male sex is usually chosen in cases where there is reason to assume the presence of androgenic activity of their own testicles. Therapy in these patients is not only substitution. Sometimes it is necessary to stimulate the function of their own gonads with gonadotropins. It should be remembered that excessively active androgen therapy can cause undesirable suppression of endogenous gonadotropic activity and, as a consequence, a decrease in the function of already defective testicles. Therefore, it is better to limit yourself to the minimum doses of androgens for a given patient, administering them in intermittent courses. In some cases, alternating treatment with androgens and gonadotropin preparations is justified. According to the literature and our observations, chorionic gonadotropin not only stimulates Leydig cells, but also increases the sensitivity of target tissues to the action of androgens. However, high doses of gonadotropins can contribute to the development of hyalinosis of the seminiferous tubules.

Approximate schemes of hormone therapy.

• Continuous replacement therapy (for female phenotype):
  • a) sinestrol 0.001 g (1 tablet) per day for 3-6-12 months;
  • b) microfollin-forte 0.05 mg (1 tablet) per day continuously;
  • c) microfollin-forte 0.05 mg (1 tablet) per day constantly, 12.5% solution of oxyprogesterone capronate 1 ml intramuscularly every 10 days for 3-6 months (if mastopathy occurs in patients without derivative Müllerian structures).
• Cyclic replacement therapy (for female phenotype):
  • a) microfollin-forte 0.05 mg (1 tablet) per day from the 1st to the 20th day of each month or from the 5th to the 26th day of the cycle;
  • b) microfollin-forte 0.05 mg (1 tablet) per day from the 1st to the 15th day of each month or from the 5th to the 20th day of the cycle, pregnin 0.01 g (1 tablet) 3 times per day sublingually from the 16th to the 21st day or from the 21st to the 26th day of the cycle;
  • c) infekundin (bisecurin, non-ovlon, etc.), 1 tablet per day from the 1st to the 21st day of each month or from the 5th to the 26th day of the cycle;
  • d) infekundin (bisecurin, non-ovlon), 1 tablet per day from the 1st to the 21st of each month or from the 5th to the 26th day of the cycle, 12.5% solution of oxyprogesterone capronate, 1 ml intramuscularly on the 16th day of infekundin administration;
  • d) methyltestosterone 0.005 g 1-2 times a day from the 1st to the 21st or from the 5th to the 26th day of the cycle for 3-4 months under the tongue (for the development of secondary hair growth).
• Androgenization (in male phenotype):
  • a) methyltestosterone 0.005-0.01 g 2-3 times a day sublingually for 1 month. Breaks between courses - 2-4 weeks;
  • b) human chorionic gonadotropin (choriogonin) 500-1500 IU intramuscularly 2-3 times a week, for a course of 10-20 injections, 2-3 courses per year;
  • c) sustanon-250 (omnadren-250) 1 ml intramuscularly once a month, constantly (in case of severe testicular insufficiency as a replacement therapy);
  • d) 10% testenate solution, 1 ml intramuscularly once every 10-15 days continuously (replacement therapy).

A medical examination of patients with congenital pathology of sexual development is a necessary condition for treatment. In prepubertal age, the frequency of visits to the doctor may not be more than once a year. Medical observation is of particular importance in prepuberty and puberty, when the question of hormonal correction of physical and sexual development arises. Starting from the age of 7-8, annual radiography of the hands and wrists is necessary to assess the dynamics of skeletal maturation. If the bone age significantly lags behind the actual age, hormonal therapy should be started earlier. The dynamics of bone age is of particular importance in patients with growth retardation receiving anabolic or sex drugs: with rapid maturation of the skeleton, a reduction in dosage or discontinuation of treatment is required. Against the background of taking sex hormones in puberty, patients should be examined at least 3-4 times a year, in postpuberty and adulthood - 2-3 times a year.

Psychological and sexological observation plays an important role in dispensary observation. Such patients have difficulty with changing doctors and communicating with other specialists. Confidential contact with their regular attending physician is especially important for them. It should be emphasized that it is necessary to maintain strict medical confidentiality of the diagnosis: involuntary disclosure of it can lead to serious excesses on the part of patients, including suicidal actions.

Outpatient monitoring should be carried out by an endocrinologist with the participation of a gynecologist, urologist and neuropsychiatrist.

The prognosis for life is favorable, in terms of social adaptation it is determined by the correctness of the choice of sex (in intersexual conditions), the adequacy of replacement and/or stimulating hormone therapy, which ensures the development of the phenotype corresponding to the chosen sex, the possibility of adaptation in society, normal sexual life and starting a family. The prognosis for stimulating fertility in the absolute majority of patients is unfavorable. Patients who retain fertility are a rare exception.

The working capacity of patients with congenital pathology of sexual development is undoubtedly limited due to the absolute or relative insufficiency of the anabolic action of sex hormones. With systematic adequate treatment, it improves. More significant limitations are sometimes observed in chromosomal diseases, Shereshevsky-Turner and Klinefelter syndromes, the "Turneroid" form of testicular dysgenesis syndrome. Some of these patients have defects not only in somatic but also in mental development, which requires the selection of a specialty corresponding to their capabilities. However, discipline, diligence and conscientiousness, characteristic of most of these patients, as a rule, ensure their work adaptation. Only individual patients, due to the peculiarities of their mental state, need to be transferred to disability.