Hyperprolactinemia as a cause of pregnancy failure

Prolactin has a structural similarity with the growth hormone, is a polypeptide, and is formed in the pituitary gland. In 1981, the prolactin gene was cloned. It is believed that it is formed from a common somatomammotropic precursor. The prolactin gene is located on chromosome 6. Synthesis and secretion of prolactin is carried out by lactotrophs of the adenohypophysis and is under the direct control of the hypothalamus. The hypothalamic-pituitary system has both an inhibitory and stimulating effect on prolactin secretion through neuroendocrine, autocrine, and paracrine mechanisms.

Several forms of circulating prolactin have been described:

1. "small" prolactin (MM-22000) with high activity;
2. "large" prolactin (MM-50000) and
3. "big-big".

"Large" prolactin and "large-large" have low affinity for receptors. It is believed that fertility is maintained by "large-large" prolactin, which can be converted into "small" in plasma. The main prolactin-inhibiting factors are dopamine (DA), γ-aminobutyric acid (GABA). Thyrotropin-releasing hormone, serotonin, opioid peptides, histamine, oxytocin, angiotensin, etc. participate in the regulation of prolactin secretion. Secretion of prolactin under physiological conditions is caused by sleep, food intake, physical exercise, and stress. In pregnant women, prolactin levels begin to increase in the first trimester of pregnancy and increase until the end of pregnancy, exceeding the pre-pregnancy prolactin level by 10 times. It is believed that this increase is due to increased estrogen levels.

The fetus begins producing prolactin at 12 weeks, with a rapid increase in the last weeks before delivery. By the end of pregnancy, the fetus's prolactin level is higher than that of the mother, but after delivery it rapidly decreases by the end of the first week of life. Prolactin is found in amniotic fluid in quantities 5-10 times higher than its plasma level. The maximum amount of prolactin is noted in the second trimester of pregnancy.

Prolactin can be synthesized by the chorion and decidual membranes. Moreover, dopamine does not affect the synthesis of prolactin by decidual tissue. It is assumed that prolactin produced by decidual tissue participates in the osmoregulation of amniotic fluid and, together with decidual relaxin, regulates uterine contractility.

Miscarriage is not associated with severe disorders of prolactin synthesis, as is observed in infertility. In patients with miscarriage, prolactin levels are slightly elevated and do not cause gallactorrhea and/or amenorrhea, but significantly disrupt the menstrual cycle due to the androgenic effect of excess prolactin. According to researchers, 40% of patients with hyperprolactinemia have a disorder of androgen secretion and metabolism. Such patients have elevated levels of DHEA and DHEA-S. The level of steroid-binding globulin is also reduced due to the effect of prolactin on the liver.

Clinical signs of hyperandrogenism are usually absent, due to an increase in less active androgens. An increase in free testosterone and androstenedione is noted only in some women. The level of free dihydrotestosterone in such patients is reduced due to a decrease in the activity of 5a-reductase (the enzyme responsible for the effect of androgens on the hair follicle) under the influence of prolactin. Elevated prolactin levels are often combined with hyperinsulinemia and may be important in the development of insulin resistance. It is believed that hyperprolactinemia can disrupt normal ovarian function. High prolactin levels in the early follicular phase inhibit progesterone secretion, and lower prolactin levels in mature follicles promote increased progesterone secretion.

According to many researchers, hyperprolactinemia causes infertility precisely because of its effect on steroidogenesis and excess androgens, but if pregnancy occurs, its course, as a rule, proceeds without significant complications.

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