HYPERPROLACTINEMIA IN THE MECHANISMS OF UTERINE LEIOMYOMA
DEVELOP (CLINICAL CASES)
T.F. Tatarchuk, MD, professor, corresponding member of NAMS of Ukraine, Deputy Director for
Research Work, Chief of the Endocrine Gynecology Department, Institute of Pediatrics, Obstetrics
and Gynecology, NAMS of Ukraine
N.V. Cossey, MD, Chief researcher at the Department of Endocrine Gynecology, Institute of
Pediatrics, Obstetrics and Gynecology, NAMS of Ukraine
L.A. Vasilchenko, graduate student, Department of Endocrine Gynecology, Institute of Pediatrics,
Obstetrics and Gynecology, NAMS of Ukraine
V.A. Dzhupin, Institute of Pediatrics, Obstetrics and Gynecology, NAMS of Ukraine
Leiomyoma (LM) is one of the most common tumors of the reproductive organs of a uterine a true benign tumor of the uterus, clinically manifested by uterine bleeding, anemia, symptoms of
organs compression, pain, and often reproductive dysfunction - infertility, miscarriage, childbirth
complications.
For a long time the main treatment for this disease was radical hysterectomy. In recent
decades we have expanded opportunities conserving therapy of this disease. This led to a drastic
reduction in the number of interventions and increases the proportion of such operations as
conservative myomectomy, uterine artery embolization (UAE), hysteroscopic resection of
submucous node.
The recurrence rate after conserving therapy of LM remains high and ranges from 2 to 50%
[21, 24]. Given the above, it is relevant issue of prevention of tumor recurrence. Active study of the
pathogenesis of hyperproliferative processes of reproductive organs in women has led to the
identification of new facts relating with the mechanism of the development of LM, among them the new data on the role of prolactin.
Modern studies have shown participation of prolactin in the mechanism of development of
breast cancer and prostate cancer, LM and endometrial hyperplasia. Its effect on the uterine tissue
implements prolactin receptors by affecting the exposed functional polymorphisms in connection
with what may appear different properties of the hormone. Prolactin receptor’s systems have been
detected in many organs and tissues, including in normal tissues endo- and myometrium and
LM[15-17]. R. Nowak et al. (1993) demonstrated that this hormone plays the role of mitogen
growth factor for the tissue leiomyoma and myometrium cells [18].
Furthermore, prolactin is synthesized locally. R. Nowak et al. (1993) demonstrated that
uterine cells secrete prolactin, which is immunologically identical to hypophyseal prolactin.
Thus, there is a dual nature of prolactin - on the one hand it is the pituitary hormone, and with
another - shows properties of cytokine realizing its effects within the tissues due to the para- and
autocrine mechanisms of regulation. These facts give reason to consider prolactin as a tumor
genesis factor.
Hyperprolactinemia can take part in the growth of LM and its recurrence after surgery,
significantly reducing the chances of women to give birth as by stimulating growth of recurrent
tumors, and by the impact of ovarian function [10-13].
Common mechanism of development of benign tumors of the uterus and mammary glands,
such as hyperprolactinemia, contribute to that is LM often combined with dyshormonal breast
diseases [4-6, 24, 28-30].
Research in our clinical have shown the presence of hyperprolactinemia in 39% of patients
with isolated growth LM, and in 48% cases of combining LM with the breast pathology [6, 32].
Assessing the level of prolactin receptor expression by immune-histochemical studies shown a
predominance of leiomyomas-prolactin-positive tumors (78.57%), especially in cases of
combination with dyshormonal breast diseases and thyroid gland.
Given the above, an important step in the treatment of LM is a control of prolactin and its
correction in the case of higher values.
In recent decades for the treatment of endocrine disorders are used natural drugs, in particular,
of vegetable origin. Especially herbals that providing specific selective receptor- modulating effect.
These drugs can be considered a means of choice in the beginning of therapy of dishormonal
disorders, including hyperprolactinemia, given their safety [6, 24, 28-30].
Special attention should attend to herbal drugs with dopaminergic action containing extract
Vítex agnus-castus – Mastodynon, Cyclodynone - well proven as agents for the treatment of
hyperprolactinemia. Thanks dopaminergic action they are inhibits the secretion of prolactin, which
helps normalize the functioning of the hypothalamic-pituitary-ovarian system [28, 29].
Given the importance of prolactin in the regulation of various processes in the body, including
the adaptation of its features, immunity while correcting hyperprolactinemia it is important to
achieve concentrations within the physiological hormone levels, while avoiding to suppress
secretion abnormally low levels.
Previously studies have shown that the use of Cyclodynone in patients with LM on the
background of increased prolactin concentrations in 86.8% of cases contributed to its normalization
within its physiological levels. Thus none of them is marked fall to low levels of the hormone
indices (1-2 ng/ml), which sometimes occurs when assigning stronger drugs. This therapy was well
tolerated and there were no cases of failure of the drug due to side effects [6, 32]. Below we
describe some clinical examples of such situation.
Clinical case 1
Patient D., 37 years old, referred to the clinic for consultation and treatment for symptomatic
LM sizes up to 16 weeks of gestation with complaints of heavy painful periods in the past five
years, an increase of the abdomen, feeling of pressure on the bladder, constipation, primary
infertility for 16 years.
Since 2006, the woman received treatment for primary infertility on the background of
chronic adnexitis. Hypothyroidism was detected, but its treatment is not carried out. During the next
gynecology inspection and gynecological ultrasound LM was diagnosed.
Ultrasonography revealed an increase in the uterus to the size 154,0 × 95,5 mm (V = 1008,5
cm ³) by intramural node on the back wall of the uterus size of 83 × 62 mm (V = 596,39 cm ³) with
severe peri- and intranodular blood flow (Fig. 1).
Fig.1. Pelvic ultrasound patient D., 37 years old: uterine fibroids befor UAE
Hyperprolactinemia was diagnosed - prolactin concentration in serum was 39.39 ng/ml.
Further examination made it possible to identify the cause of hyperprolactinemia - hypothyroidism.
It is known that thyrotropin-releasing hormone, the synthesis of which is increased by the lack of
thyroid hormone in the pituitary gland stimulates the production of prolactin.
Given the large size of fibroids, reproductive history (no pregnancies) and women's interest in
saving the uterus, it was decided to carry out a two-stage treatment of LM: I stage - UAE as
preoperative preparation, II stage - conservative myomectomy.
In the preoperative period the correction of hormonal homeostasis was done. To reduce the
level of prolactin Cyclodynone was appointed 1 tablet 1 time a day under the control of the
hormone concentration. It should be noted that the level of prolactin in 1 month after Cyclodynone
intake dropped to 35 ng/mL after 3 months - up to 29 ng/mL after 6 months the level was 19 ng/mL,
indicating that the positive dynamics and efficiency of Cyclodynone in hyperprolactinemia
correction (Table 1).
Table 1. Results of the examination of the patient D., 37 years old
Indicators
Results
Reference values
Somatomedin C, ng / ml
73 (below normal)
116-385
Carcinoembryonic antigen, ng / ml
1,07
< 2,5
CYFRACA 21-1
2,36
< 2,82
(cytokeratin 19 fragment), ng / ml
AntiMullerian hormone, ng / ml
2,51
0,85-14,24
Prolactin, ng / ml
39,39 (above normal)
2,8-29,2
After Cyclodynone 1 tablet once a day
Prolactin after 1 month, ng / ml
35 (above normal)
2,8-29,2
Prolactin 3 months, ng / ml
29
2,8-29,2
Prolactin after 6 months, ng / ml
19
2,8-29,2
Prolactin after 1 year, ng / ml
17
2,8-29,2
L-thyroxin at a dose of 50 mg / day was appointed for hypothyroidism, followed by clinical
observation and correction of the dose depending on the hormonal homeostasis.
During treatment bilateral UAE was performed. Postembolization period was uneventful.
Postoperatively antibiotic, infusion, anti-inflammatory, symptomatic therapy was prescribed,
probiotics and hepatoprotectors for prevention of thromboembolic complications were prescribed.
One month after embolization in the patient was diagnosed reducing the size of the uterus and the
node by 12% (Fig. 2).
1.5 months after UAE routinely made conservative myomectomy (Figure 3 - a, 3 - b).
Fig.2. Pelvic ultrasound, patient D., 37 years, uterine fibroid after embolization
Figure 3-a. Patient D., 37 years old: conservative myomectomy
Fig. 3 - b. Patient D., 37 years old: the uterus after layering restore its integrity
On the fifth day after surgery to contraception and prevention hypermenorrhea was introduced
intrauterine system Mirena. The patient continued to intake Cyclodynone under control of prolactin
levels, dynamic control confirmed a gradual decline it to the reference values.
After treatment the patient menstruated regularly after 28 days of menstruation with duration
of 5-7 days, painless and scanty.
Ultrasound at 3 months after surgery showed a reduction of uterus compared with the original
value at 93.23% - up to size 73,9 × 46,2 mm (V = 68,28 cm³); myometrium was more
heterogeneous in the postoperative scar, in the uterus visualized intrauterine system Mirena (Fig. 4).
Figure 4. Pelvic ultrasound, patient D., 37 years old: the uterus after 3 months after
conservative myomectomy
1 year after the operation ultrasound showed no pelvic pathology (Fig. 5) - reducing the
uterine 96.38% of the original volume to the size 45,3 × 40,3 mm (V = 36,51 cm ³), myometrium
visualized uniform, Mirena was in the uterus. Prolactin stable level was confirmed - 17 ng / ml.
After 2 years (after Mirena removal) there was a pregnancy that ended by the birth of a child
in term by cesarean section.
Figure 5. Pelvic ultrasound, patient D., 37 years old: the uterus 1 year after conservative
myomectomy
Clinical case 2
Patient D., aged 36, was admitted to hospital complaining on meno- and metrorrhagia, feeling
the pressure on the bladder, frequent urination during the last six months, secondary infertility.
There was a psycho-emotional lability women with hysteroid personality type.
From the history: at 25 years was physiological labor and at 28 years - medical termination of
pregnancy 6-7 weeks. In 2008 woman suffered a lot of stress, and then was soon diagnosed LM.
Patient notes mood instability, irritability. Furthermore, the presence of the tumor and secondary
infertility in a second marriage were traumatic factors for her.
Woman observed in clinic since 2009 about secondary infertility and LM. It has been a
gradual increase in tumors from 5 to 12 weeks of pregnancy.
At the time of examination and pelvic ultrasound in our clinic revealed: uterus size 114,2 ×
109,8 mm (V = 626,96 cm3), increased in size due to the intramural myoma node, located on the
back wall, size 88,2 × 76,5 mm (V = 236,16 cm3); heterogeneous endometrium due to the formation
of increased echogenicity size 15mm (endometrial polyp), right ovary 32 × 19 mm, left ovary 29 ×
17 mm (Fig. 6). Breast ultrasound diagnosed diffuse fibrocystic breast hyperplasia. Ultrasound
sowed no thyroid pathology.
Figure 6. Pelvic ultrasound, patient D., 36 years old: uterine fibroids befor UAE
In 2009 hyperprolactinemia was detected up to 35 ng / ml, but doctors at that time did not pay
attention on it. Accordingly, the concentration of prolactin in the future have not been adjusted.
In 2012 prolactin was 43 ng / ml, on the basis of what it could be concluded a long time
hyperprolactinemia. Moderate increase of prolactin concentration indicates more in favor of a
functional nature, possibly stress-induced. It is possible that elevated levels of prolactin promoted a
tumor growth.
Laboratory tests showed anemia III degree. The complex anti-stress, antianaemia, antiinflammatory, immunomodulatory therapy was done.
To reduce the level of prolactin was Cyclodynone prescribed 1 tablet once a day on a
background of antistress therapy. After 1 month of Cyclodynone intake prolactin index fell to
31ng/ml, after 3 months - up to 28 ng / ml, after 6 - to 14 ng / ml, indicating the adequacy of the
prescribed therapy (Table 2).
Table 2. Results of the examination of the patient D., 36 years old
Indicators
Results
2009 year
Prolactin, ng / ml
35 (above normal)
2012 year
Somatomedin C, ng / ml
213
Carcinoembryonic antigen, ng / ml
0,98
CYFRACA 21-1
2,1
(cytokeratin 19 fragment), ng / ml
AntiMullerian hormone, ng / ml
1,8
Prolactin, ng / ml
43 (above normal)
After Cyclodynone 1 tablet once a day
Prolactin after 1 month, ng / ml
31 (above normal)
Prolactin 3 months, ng / ml
29
Prolactin after 6 months, ng / ml
14
Prolactin after 1 year, ng / ml
20
Reference values
2,8-29,2
116-385
< 2,5
< 2,82
0,8-14,24
2,8-29,2
2,8 - 29,2
2,8 - 29,2
2,8 - 29,2
2,8 - 29,2
Separate diagnostic curettage of the cervical canal and the walls of the uterus were made.
Endocervical hyperplasia in the cervical canal and stromal-glandular endometrial polyp in the
uterine cavity were revealed. Antianemia therapy continued and at the time of treatment Hb was
raise to 108 g / l.
Bilateral UAE was performed. The postoperative period was uneventful.
1 month after UAE patient admitted to the Department about the nascent of myoma node on the
background postembolization syndrome, with anemia moderate severity the second degree.
According to the ultrasound a month after the UAE there were a decrease of the uterus at 25.37% up to size 104,1 × 9,9 mm (V = 467,93 cm3) due to decrease of myoma node by 25.57% - up to size
87,2 × 73.3 mm (V = 175,78 cm3) (Fig. 7).
Figure 7. Pelvic ultrasound, patient D., 36 years, after uterine fibroid embolization, with a tendency
to the birth of a node
The patient received anti-inflammatory, antibacterial, infusion, detoxifying, antianaemia
therapy, it was also sanitization of the uterus and vagina cavities. On the background of the above
complex treatment was done a removing necrotic tissue myoma node with curettage of the uterine
cavity (Fig. 8). Histopathological examination result: nodal LM with degenerative changes,
hemorrhages and ischemic necrosis macrofocal node.
Ultrasound a week after removal of myoma node showed a decrease of the uterus to 79.82%
of the original volume - up to size 73,6 × 57,3 mm (V = 126,5 cm3) (Fig. 9).
1 month after removal of uterine myoma node sizes was 47,6 × 34,4 mm (V = 2,75 mm3) - a
decrease of 94.78% from the initial value (Fig. 10).
Due to systemic Cyclodynone intake on the above scheme for 6 months it was achieved a
stable therapeutic effect - normal levels of prolactin, confirmed after one year of therapy (6 months
after withdrawal) - 20 ng / ml.
Figure 8. The removed tissue of necrotic
Figure 9. Pelvic ultrasound, patient D.,
myoma node
36 years old: the uterus on the third day after
the removal of the embolized myoma node
Figure 10. Pelvic ultrasound, patient D., 36 years old: uterus after 1 month after removal of
the embolized myoma node
CONCLUSIONS
Hormonal and immunological disorders that persist after removal of the tumor and
underlying the development of LM, can cause tumor recurrence and significantly impair
reproductive prognosis after myomectomy. Therefore planning of the LM treatment by any organsaving method should include examination of all possible etiologic factors at the preoperative stage
with their timely correction.
The studies have shown that correction of hyperprolactinemia can be considered as a
legitimate component of the complex pathogenetic treatment of uterine leiomyoma and the
prevention of its growth. The main objective of treatment in cases of small size uterine leiomyoma
is a stabilization of tumor size and preventing its rapid growth and normalization of hormonal
status.
Herbal remedies with dopaminergic activity (in particular Cyclodynon) against antistress
therapy are an effective method of correction in patients with uterine leiomyoma and mild
functional hyperprolactinemia. Normalization of hormonal homeostasis stabilizes the effectiveness
of the LM treatment, preventing recurrence of the tumor and creates conditions for the recovery of
reproductive function of women after breast-saving surgery.
HYPERPROLACTINEMIA IN THE MECHANISMS OF UTERINE LEIOMYOMA
DEVELOP (CLINICAL CASES)
T.F.Tatarchuk, MD, professor, corresponding member of NAMS of Ukraine, Deputy Director for Research
Work, Chief of the Endocrine Gynecology Department, Institute of Pediatrics, Obstetrics and Gynecology,
NAMS of Ukraine
N.V. Cossey, MD, Chief researcher at the Department of Endocrine Gynecology, Institute of Pediatrics,
Obstetrics and Gynecology, NAMS of Ukraine
L.A. Vasilchenko, graduate student, Department of Endocrine Gynecology, Institute of Pediatrics,
Obstetrics and Gynecology, NAMS of Ukraine
V.A.Dzhupin, Institute of Pediatrics, Obstetrics and Gynecology, NAMS of Ukraine
The studies have shown that correction of hyperprolactinemia can be considered as a
legitimate component of the complex pathogenetic treatment of uterine leiomyoma and the
prevention of its growth. The main objective of treatment in cases of small size uterine leiomyoma
is a stabilization of tumor size and preventing its rapid growth and normalization of hormonal
status.
Herbal remedies with dopaminergic activity (in particular Cyclodynon) against antistress
therapy are an effective method of correction in patients with uterine leiomyoma and mild
functional hyperprolactinemia.
Keywords: uterine leiomyoma, prolactin, Cyclodynon.
ГІПЕРПРОЛАКТИНЕМІЯ
МАТКИ (КЛІНІЧНІ ВИПАДКИ)
У
МЕХАНІЗМІ
РОЗВИТКУ
ЛЕЙОМІОМИ
Т.Ф. Татарчук, д. мед. н., професор, член-кор. НАМН України, заступник
директора з наукової роботи, зав. відділенням ендокринної гінекології Інституту педіатрії,
акушерства та гінекології НАМН України
Н.В. Косей, д. мед. н., головний науковий співробітник відділення ендокринної
гінекології Інституту педіатрії, акушерства та гінекології НАМН України
Л.О. Васильченко, молодший науковий співробітник відділення ендокринної
гінекології Інституту педіатрії, акушерства та гінекології НАМН України
В.О. Джупін, Інститут педіатрії, акушерства і гінекології НАМН України
Результати проведених досліджень показали, що корекцію гіперпролактинемії
можна вважати патогенетично обгрунтованою складовою комплексного лікування
лейоміоми матки (ЛМ) і профілактики її рецидивів. У випадках наявності лейоміоми матки
невеликих розмірів, коли основною метою лікування є стабілізація розмірів пухлини і
профілактика швидкого її зростання, особливе значення має нормалізація гормонального
статусу.
У пацієнток з лейоміомою матки і помірною гіперпролактинемією функціонального
характеру ефективним методом корекції є призначення фітопрепаратів дофамінергічної дії,
зокрема, Циклодинону, на фоні антистрессорного терапії.
Ключові слова: лейоміома матки, пролактин, Циклодинон.
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