Gonadotropic insufficiency

Gonadotropic insufficiency is a form of anovulatory infertility characterized by damage to the central links of the reproductive system, leading to a decrease in the secretion of gonadotropic hormones.

GnRH secretion by the hypothalamus is key in establishing and maintaining normal gonad function.

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Epidemiology

Gonadotropic insufficiency occurs in 15–20% of women with amenorrhea.

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Stages

Depending on the results of the hormonal study, the following degrees of severity of gonadotropic insufficiency are distinguished:

• mild (LH 3.0–5.0 IU/L, FSH 1.75–3.0 IU/L, estradiol 50–70 pmol/L);
• average (LH 1.5–3.0 IU/l, FSH 1.0–1.75 IU/l, estradiol 30–50 pmol/l);
• severe (LH < 1.5 IU/L, FSH < 1.0 IU/L, estradiol < 30 pmol/L).

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Forms

The following forms of gonadotropic deficiency are distinguished:

• hypothalamic;
• pituitary.

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Diagnostics gonadotropic insufficiency

The absence of estrogen influence on the female body causes characteristic features of the phenotype: eunuchoid body type - tall stature, long limbs, sparse hair growth on the pubis and in the armpits, hypoplasia of the mammary glands, labia, decreased size of the uterus and ovaries. The severity of clinical symptoms depends on the degree of gonadotropic insufficiency.

Clinically, amenorrhea is characteristic of patients with gonadotropic insufficiency: primary in 70% of cases, secondary in 30% of cases (more characteristic of the hypothalamic form).

Special research methods

• The diagnosis is established based on the results of a hormonal study. Typically, the serum levels of LH (< 5 IU/L), FSH (< 3 IU/L) and estradiol (< 100 pmol/L) are low, with normal concentrations of other hormones.
• Ultrasound of the pelvic organs (to determine the degree of hypoplasia of the uterus and ovaries).
• Lipidogram.
• Study of bone mineral density (to identify and prevent possible systemic disorders due to long-term hypoestrogenism).
• Examination of the spouse's spermogram and the patency of the woman's fallopian tubes in order to exclude other factors of infertility.

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Differential diagnosis

For differential diagnostics of hypothalamic and pituitary forms of gonadotropic insufficiency, a test with a gonadotropin-releasing hormone (GnRH) agonist (e.g., triptorelin intravenously 100 mcg once) is used. The test is considered positive if, in response to the administration of drugs (LS), an increase in LH and FSH concentrations by at least 3 times is noted at the 30-45th minute of the study. A negative test indicates a pituitary form of insufficiency, a positive test indicates preserved pituitary function and damage to the hypothalamic structures.

Treatment gonadotropic insufficiency

Treatment of infertility due to gonadotropic insufficiency is carried out in 2 stages:

• Stage 1 - preparatory;
• Stage 2 - ovulation induction.

At the preparatory stage, cyclic hormone replacement therapy is carried out to form a female phenotype, increase the size of the uterus, proliferate the endometrium, activate the receptor apparatus in target organs, which increases the effectiveness of subsequent ovulation stimulation. The use of natural estrogens (estradiol, estradiol valerate) and gestagens (dydrogesterone, progesterone) is preferable. The duration of preparatory therapy depends on the severity of hypogonadism and is 3-12 months.

Drugs of choice:

• estradiol orally 2 mg 1-2 times a day, course 15 days or
• estradiol valerate orally 2 mg 1-2 times a day, course 15 days, then
• dydrogesterone orally 10 mg 1-2 times a day, course 10 days or
• progesterone orally 100 mg 2-3 times a day, or vaginally 100 mg 2-3 times a day, or intramuscularly 250 mg 1 time per day, course 10 days. The introduction of estrogens begins on the 3rd-5th day of the menstrual-like reaction.

Alternative drugs:

Scheme 1:

• estradiol 2 mg once a day, course 14 days, then
• estradiol/dydrogesterone 2 mg/10 mg once a day, course 14 days.

Scheme 2:

• estradiol valerate orally 2 mg once a day, course 70 days, then
• estradiol valerate/medroxyprogesterone orally 2 mg/20 mg once a day, course 14 days, then
• placebo 1 time per day, course 7 days. Scheme 3:
• estradiol valerate orally 2 mg once a day, course 11 days;
• estradiol valerate/norgestrel orally 2 mg/500 mcg once a day, course 10 days, then a break of 7 days.

After completion of the first stage, ovulation induction is performed, the main principles of which are an adequate choice of the drug and its starting dose and careful clinical and laboratory monitoring of the stimulated cycle.

The drugs of choice at this stage are menotropins.

• Menotropins IM 150-300 IU once a day at the same time from the 3rd to the 5th day of the menstrual-like reaction. The starting dose depends on the severity of gonadotropic insufficiency. The adequacy of the dose is assessed by the dynamics of follicle growth (normally 2 mm/day). With slow follicle growth, the dose is increased by 75 IU, with too rapid growth, it is reduced by 75 IU. The drug is administered until mature follicles with a diameter of 18-20 mm are formed, then human chorionic gonadotropin IM 10,000 IU is administered once.

After ovulation has been confirmed, the luteal phase of the cycle is supported:

• dydrogesterone orally 10 mg 1-3 times a day, course 10-12 days or
• progesterone orally 100 mg 2-3 times a day, or vaginally 100 mg 2-3 times a day, or intramuscularly 250 mg 1 time per day, course 10-12 days.

In the absence of symptoms of ovarian hyperstimulation, it is possible to use:

• human chorionic gonadotropin intramuscularly 1500–2500 IU once a day on days 3.5 and 7 of the luteal phase.

If the first course is ineffective, repeated courses of ovulation induction are carried out in the absence of ovarian cysts.

An alternative scheme for ovulation induction is the use of GnRH agonists (effective only in the hypothalamic form), which are administered intravenously from the 3rd to 5th day of the menstrual-like reaction for 20-30 days in a pulsating mode (1 dose for 1 min every 89 min) using a special device. If the first course is ineffective, repeated courses of ovulation induction are carried out in the absence of ovarian cysts.

It is not advisable to use antiestrogens to induce ovulation in cases of gonadotropic insufficiency.

Forecast

The effectiveness of treatment depends on the degree of gonadotropic insufficiency, the woman’s age and the adequacy of preparatory therapy.

In the pituitary form of gonadotropic insufficiency, induction of ovulation with menotropins leads to pregnancy in 70–90% of women.

In the hypothalamic form, ovulation induction with menotropins is effective in 70% of women, and induction with pulsatile administration of a GnRH agonist is effective in 70–80% of women.

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