Chiari Frommel syndrome is a variant of hyperprolactinemic hypogonadism that occurs in women of reproductive age. It is manifested by opso-oligomenorrhea, amenorrhea, lactorrhea, infertility, sexual disorders, hirsutism. It is diagnosed on the basis of laboratory data on the content of prolactin, estrogens, progestins, thyroid hormones, adrenal glands, CT results, MRI of sella turcica. DA-receptor agonists, dopamine precursors, and serotonin receptor blockers are used for treatment. In the presence of pituitary macroadenomas, their surgical removal or X-ray destruction is performed.
ICD 10
E22.1 N91.1 N64.3
General information
Prevalence of persistent galactorrhea-amenorrhea (hyperprolactinemic hypogonadism,, Forbes-Albright, Ayumada-Argons-del Castillo) in women, it reaches 0.1%. Mostly young patients aged 20-35 years get sick, in adolescents, elderly patients, the disorder is diagnosed extremely rarely. As a separate pathological condition, CFS was first described in 1855 by Austrian scientists G. Chiari, K. Brown, J. Spat, in 1882, the connection of pathology with the endocrine failure of the body was established. In recent years, the number of atypical forms of the disorder has been increasing: with a normal concentration of hyperactive forms of prolactin or hypersensitivity to the hormone of mammary gland tissues, the absence of lactorrhea and amenorrhea with a high content of lactotropic hormone having a low bioeffect, galactorrhea without amenorrhea with hypersecretion of mammotropin with small molecule sizes.
Causes
The disorder develops against the background of increased prolactin content in the blood. The genesis of hyperprolactinemia is heterogeneous. Galactorrhea syndrome can occur when any link of neuroendocrine regulation affecting the synthesis of mammotropic hormone is affected. Specialists in the field of endocrine gynecology distinguish the following groups of causes that cause galactorrhea-amenorrhea:
- Pathology of the hypothalamus. Violations of the hypothalamic regulation of prolactin synthesis can be both organic and functional. Hyperprolactinemic syndrome is observed in xanthomatosis, sarcoidosis, histiocytosis X, decompensation of a congenital defect of the tuberoinfundibular zone with impaired secretion of dopamine, less often — vasoactive intestinal peptide.
- Diseases of the pituitary gland. Hyperprolactinemia with galactorrhea and amenorrhea is observed in patients with micro- and macroprolactinomas producing excessive amounts of lactotropic hormone. Hypersecretion is also possible with pituitary gland, compression of the pituitary pedicle by hormone-inactive tumors, its cutting, which contributes to disruption of dopamine transport through axons or capillaries.
- Concomitant diseases. Mammotropin secretion is regulated not only by dopamine, but also by sex hormones, endogenous steroids, tyroliberin, prostaglandins. Therefore, symptomatic forms of persistent galactorrhea are formed against the background of endocrine disorders (Stein-Leventhal syndrome, adrenogenital syndrome, primary hypothyroidism), liver and kidney failure.
- Taking medications. Prolactin levels increase with prolonged use of dopamine blockers, phenothiazine—type neuroleptics, tricyclic antidepressants, antihypertensive drugs, metoclopramide, opioids. Hyper-inhibition of the gonadotropic function of the pituitary gland is noted after the cancellation of some COCs with a high content of estrogen.
- Prolactin secretion by other tissues. It has been established that mammotropin is produced by cells of some malignant neoplasms, proximal tubules of the kidneys, endometrium, intestinal mucosa, skin, and other tissues. This explains the occurrence of Chiari Frommel Syndrome in cancer of the cervix, tongue, rectum, lungs, multiple sclerosis, acute myeloid leukemia, rheumatoid arthritis.
- Stressful loads. The inhibitory effect of the hypothalamus on the secretion of lactogenic hormone can be weakened by acute and chronic stress, debilitating physical exertion. The role of emotional causes and unfavorable environmental factors is especially great at puberty, when negative influences and stresses prevent the normal formation of the menstrual cycle.
Convincing facts confirming the hereditary nature of the syndrome have not been revealed. Although in isolated cases hyperprolactinemia with signs of galactorrhea-amenorrhea was observed in sisters, the incidence of the disorder in relatives practically does not differ from the indicators in the general population. Changes at the level of the genetic apparatus have also not yet been detected.
Pathogenesis
The key link in the development of persistent galactorrhea-amenorrhea syndrome is the increased pituitary or extrahypophysial synthesis of prolactin. Hypersecretion of mammotropin by the pituitary gland is caused by a decrease in the production and impaired transport of dopamine, which inhibits the release of lactotropic hormone, increased synthesis of VIP, which performs the function of prolactoliberin, hyperplasia and hyperactivity of prolactocytes. The level of the hormone also increases when it is formed by cells of other tissues, mainly malignant tumors. Against the background of constant or frequent transient hyperprolactinemia, the lactogenic function of the mammary glands is stimulated, the cyclic secretion of gonadotropins and luteinizing hormone is disrupted, which leads to the suppression of ovarian tissue cells, the development of amenorrhea, hypogonadism.
Classification
The systematization of forms of CFS, developed by domestic endocrinologists, is based on the etiology of persistent galactorrhea. This approach allows us to develop optimal therapeutic tactics aimed at achieving a therapeutic effect in a particular patient. The following variants of hyperprolactinemic hypogonadism syndrome with lactorrhea-amenorrhea are distinguished:
- Primary hyperprolactinemia. This group includes forms of the disease caused by disorders at the level of the central nervous system — functional and organic disorders of hypothalamic regulation, the presence of pituitary adenomas, chronic intracranial hypertension, “empty” Turkish saddle syndrome. Variants of primary Chiari Frommel syndrome are also a combination of hyperprolactinemia with other hypothalamic-pituitary pathology (acromegaly, Itsenko-Cushing’s disease, Nelson syndrome, disseminated systemic diseases).
- Secondary hyperprolactinemia. Symptomatic galactorrhea-amenorrhea is spoken of during the development of the disease against the background of extracerebral disorders. The group consists of variants of Chiari Frommel syndrome that arise due to damage to the thyroid gland, ovaries, adrenal cortex, renal and hepatic insufficiency, iatrogenic effects, the presence of extrahypophysial prolactin-secreting tumors, stress loads. Usually in such cases persistent lactorrhea-amenorrhea aggravates the symptoms of the underlying pathological process.
Symptoms
Patients with Chiari Frommel syndrome usually complain of a disturbed menstrual cycle. Monthly periods are shortened to 1-2 days, intermenstrual intervals exceed 35 days, spotting is scarce, secondary amenorrhea is possible. Copious menstruation is observed only with secondary persistent galactorrhea, which occurred against the background of primary hypothyroidism. In 20% of patients, irregular menstruation is noted from the moment of menarche, which often occurs after 15-16 years. Delays in menstruation are provoked by severe conflicts, long-term illnesses, emotional experiences during exams and in other difficult situations. Amenorrhea often develops after the beginning of intimate life, the cancellation of combined oral contraceptives, abortions, childbirth, abdominal operations, and the installation of an IUD.
Only in 20% of patients, the first symptom of the disease becomes transient or permanent lactorrhea, which persists for more than 2 years after the previous birth or is not associated with pregnancy. The intensity of galactorrhea varies from single drops with strong compression to copious, jet discharge of milk-like secretions from the nipples with light pressure and its spontaneous expiration. A common complaint with hyperprolactinemia syndrome is primary or secondary infertility, spontaneous miscarriages at 8-10 weeks of pregnancy. Women with galactorrhea-amenorrhea have sexual disorders: decreased sexual desire, anorgasmia, frigidity, dyspareunia. Patients note excessive hair on the face, around the areoles, along the white line of the abdomen.
With the primary pituitary genesis of galactorrhea syndrome, migraine—like headaches, dizziness are possible, rarely visual disturbances (the appearance of sparks, flickering of flies, loss of visual fields). With Chiari Frommel syndrome, emotional disorders in the form of increased anxiety, a tendency to subdepressive reaction, nonspecific complaints of weakness, fatigue, pulling pains in the precardial region that do not have a clear localization and do not radiate, as well as light pasty eyelids, face, feet, shins are not uncommon.
Complications
In addition to neuroendocrine infertility, the disorder is complicated by secondary hypoestrogenism with hypotrophic and atrophic changes in the genitourinary organs, early menopause, breast involution, osteoporosis, virilization. Copious lactorrhea can cause inflammatory diseases of the breast and nipple — telitis, areolitis, mastitis. With the intensive growth of tumors of the hypothalamus and pituitary gland, symptoms of increased intracranial pressure, visual impairment up to complete blindness, malignancy are possible. Long-term consequences of hyperprolactinemia are mastopathy, other benign breast dysplasia, breast cancer, disorders of fat metabolism (dyslipoproteinemia), decreased glucose tolerance and the development of diabetes mellitus.
Diagnostics
The main tasks of the diagnostic search in women complaining of amenorrhea, infertility and persistent galactorrhea are to identify the relationship of the disorder with hyperprolactinemia and clarify the causes of the disease. Taking into account the existence of etiologically different forms of CFS, the patient is prescribed a comprehensive examination, including such methods as:
- Determination of prolactin level. The content of mammotropin in the blood with persistent lactorrhea is increased by 3-5 or more times. In order to avoid mistakes, the study is recommended to be carried out repeatedly using inhibitory and stimulating hormone release tests (with dopamine, cerucal, insulin, cimetidine).
- Study of the content of other hormones. Usually there is a normal or reduced concentration of FSH, LH with a good reaction to the administration of lyuliberin. Estradiol and progesterone levels are reduced, the content of DEA-sulfate is increased. In primary hypothyroidism, the concentration of total thyroxine and triiodothyronine decreases.
- Tomography of sella turcica. With the help of MRI, CT, MSCT, volumetric formations in the pituitary gland are detected. The advantage of tomographic examination in comparison with radiography is the possibility of detecting microprolactin that are not available for diagnosis by traditional radiation methods.
In patients who have been ill for a long time, signs of uterine hypoplasia, vaginal dryness, negative symptoms of “mucus tension” and “pupil” are found during gynecological examination. The involution of the internal genitalia is confirmed by the results of ultrasound of the pelvic organs. Differential diagnosis is carried out with diseases in which hyperprolactinemia develops. As additional screening methods, radiography of the lungs, ultrasound of the kidneys, liver, adrenal glands, cortisol levels, ACTH are recommended. According to the indications, the patient is consulted by an endocrinologist, neurologist, neurosurgeon, oculist, mammologist, urologist, nephrologist, gastroenterologist, hepatologist, proctologist, oncologist.
Treatment
The choice of medical tactics is determined by the causes that caused Chiari Frommel syndrome, the severity of symptoms, and the patient’s reproductive plans. If pituitary microadenoma is detected with minimal clinical symptoms and prolactin content of no more than 100 ng / ml, dynamic monitoring of the woman’s condition is possible. Indications for therapeutic measures are the patient’s desire to become pregnant, clinically significant opsooligomenorrhea or amenorrhea with signs of hypoestrogenism, severe sexual disorders, intense lactorrhea. The main method of treatment is drug therapy aimed at reducing the level of mammotropin and correcting the symptoms of amenorrhea, persistent lactorrhea, and other manifestations of hyperprolactinemic syndrome due to this. The most effective:
- Dopamine receptor agonists. Semi-synthetic ergot alkaloids, acting on dopamine receptors, inhibit the release of lactogenic hormone. With constant intake, complete restoration of menstrual and fertile functions is possible. They reduce the size of prolactotrophs, therefore they are effective for microprolactinomas.
- Precursors of dopamine. Inhibit the secretion of prolactin by increasing the concentration of dopamine in the central nervous system. Due to the direct effect on the alveolocytes of the mammary glands, they are effective in normoprolactinemic forms of lactorrhea. They are usually prescribed on trial for 2-3 months, in the absence of improvements, they are replaced with another drug.
- Serotonin receptor blockers. With respect to the secretion of mammotropic hormone, they have a moderate dopamine-like effect. The effect of drugs of this group is based on a decrease in the inhibitory effect of serotonin on hypothalamic activity. Less effective than DA-mimetics and synthetic dopamine precursors.
Despite the information about inhibition of prolactin secretion by glucocorticoids and gamma-aminobutyric acid, the agents of these groups are not yet used in the treatment of persistent galactorrhea with amenorrhea. In the treatment of infertility, the drug regimen is supplemented with ovulation stimulants. The presence of macroprolactin and rapidly growing pituitary adenomas serves as an indication for surgical treatment – transcranial or transnasal removal of the tumor, stereotactic radiosurgery. The detection of signs of inflammatory-infiltrative brain damage is the basis for the appointment of anti-inflammatory, dehydrating, resorbing agents.
Prognosis and prevention
With timely detection and adequate treatment of Chiari Frommel syndrome, reproductive functions can fully recover. Patients with diagnosed hyperprolactinemic galactorrhea-amenorrhea are shown to be examined by an endocrinologist, and if pituitary tumors are detected, by a neurosurgeon. Prolactin levels are monitored 2-4 times a year, and MRI or CT scans are performed every 1-3 years. Every 6 months, the patient is examined by an optometrist and an obstetrician-gynecologist. For preventive purposes, women with a disturbed menstrual cycle are not recommended to prescribe drugs that can enhance the production of lactotropic hormone. In the presence of endocrine and somatic diseases complicated by hyperprolactinemia, correct corrective and replacement therapy is necessary.
