Comorbidity in gynecological practice: focus on blood vessels

Chronic venous diseases are common pathologies that affect 20 to 25% of women. In particular, among gynecological patients, about 15% of women aged 20 to 50 have pelvic vein dysfunction of varying severity. The lack of definitively established medical terms, defined imaging criteria, ambiguity of cause-and-effect relationships, and hypotheses based on small samples of clinical studies have raised doubts about the identification of pathologies such as pelvic congestion syndrome and pelvic venous disorder. The latter covers a range of venous disorders that can lead to chronic pelvic pain, mainly in women. Special attention to venous dysfunction should be paid not only by vascular surgeons but also by obstetricians-gynecologists, since a large number of modern women live with this disease without a definitive diagnosis and, as a result, without receiving appropriate treatment.

On March 27-29, a hybrid congress of vascular surgeons, phlebologists, and angiologists of Ukraine, “Sukharevsky Readings,” was held, at which leading domestic specialists discussed the diagnosis of chronic venous diseases, the specifics of their conservative treatment, and the management of patients with this profile from an interdisciplinary approach. Corresponding member of the National Academy of Medical Sciences of Ukraine, president of the All-Ukrainian Association of Gynecologists-Endocrinologists, deputy director for scientific work and head of the department of endocrine gynecology at the All-Ukrainian Center for Motherhood and Childhood of the National Academy of Medical Sciences of Ukraine, Doctor of Medical Sciences, Professor Tetiana Feofanivna Tatarchuk presented a report entitled “Comorbidity in gynecological practice: focus on blood vessels,” in which she highlighted all the controversial issues regarding pelvic vein disorders and the consequences of pelvic venous congestion syndrome.

Keywords: chronic pelvic pain, pelvic venous congestion syndrome, venous insufficiency, micronized purified flavonoid fraction, Normoven 1000.

The relationship between gynecological diseases and vascular dysfunction is a topical issue in gynecological practice. In general, there are two categories of patients in whom gynecologists must take into account the condition of the blood vessels when choosing a treatment strategy for many disorders of the reproductive system:

• women with established vascular changes or a high risk of vascular damage: use of combined oral contraceptives, menopausal hormone therapy in individuals with varicose veins, vascular thrombosis, and/or a history of thromboembolism;
• women with reproductive system disorders against the background of pelvic venous congestion syndrome (syndrome of stagnation in the pelvic organs).

The condition of the venous vessels in the pelvic organs directly affects the course of gynecological pathologies. In addition, 30-45% of women with chronic pelvic pain may have symptoms of venous insufficiency.

Pelvic pain of venous origin is pain in the pelvic area lasting more than 6 months, which manifests itself mainly as vague pain with periodic intensification, mainly after prolonged standing, physical exertion, or as dyspareunia. It is usually constant pain, not related to the menstrual cycle.

Chronic pelvic pain can be secondary in nature and occur against the background of the following pathologies: endometriosis, uterine fibroids, malignant tumors, adenomyosis, uterine prolapse, irritable bowel syndrome, and pelvic venous insufficiency. On the other hand, pelvic congestion syndrome can occur alone or in combination with varicose veins of the vulva and/or venous insufficiency of the lower extremities (Kaufman C. et al., 2021; Besile A. et al., 2021).

Causes of venous dysfunction in women of reproductive age

According to statistics, 39% of women have a history of pelvic congestion syndrome; in 30% of patients with chronic pelvic pain, pelvic congestion is diagnosed as the sole cause of pain, and another 15% suffer from it along with other pelvic organ pathologies (most often uterine fibroids). Pelvic congestion syndrome mainly affects women of reproductive age (20-45 years), and its frequency is closely related to the number of pregnancies.

In most cases, venous insufficiency occurs during pregnancy for two reasons: enlargement of the uterus with subsequent hypertension in the veins of the lower extremities, stretching and insufficiency of the valves, which impedes blood flow from the pelvic veins, as well as increased secretion of hormones that weaken the walls of the veins. Higher levels of estradiol in the blood serum during pregnancy are associated with vein distensibility and clinical signs of varicose veins in menopausal women. During pregnancy, there is also a 60% increase in the capacity of the pelvic veins, accompanied by dilation of the ovarian veins (Antignani P. L. et al., 2019).

Increased blood volume, dilation of the veins of the ovaries and pelvis during pregnancy, as well as compression of the vessels by the uterus, leads to irreversible dilation of the veins and damage to the valves, manifested by reflux.

Pelvic congestion syndrome has a multifactorial origin. In particular, genetic predisposition, anatomical features, and hormonal factors significantly affect the functioning of venous vessels.

Pelvic venous blood flow is provided by a large number of vessels and plexuses. The main vessels responsible for venous outflow from the female pelvic organs are the ovarian veins, as well as the common, external, and internal iliac veins. The uterine venous plexus (UVP) flows through the right and left uterine veins (RUV, LUV) into the internal iliac veins (RIIV, LIIV), which anastomose with the external iliac veins (EIV), transforming into the common iliac veins (CIV). The UVP anastomoses with the ovarian venous plexus (OVP), which flows into the ovarian veins. The left ovarian vein (LOV) almost always flows into the left renal vein, while the right ovarian vein (ROV) flows into the inferior vena cava, although it can flow into the right renal vein (10% of cases). Valves may be absent in the left (13-15% of cases) and right (6%) ovarian veins.

Pelvic venous congestion syndrome occurs as a result of primary anatomical venous abnormalities, such as valve deficiency and venous insufficiency, and as a consequence of secondary mechanical factors that cause venous obstruction. It is believed that venous hypertension and vasodilation due to valve insufficiency (e.g., ovarian, iliac veins) or stenosis/obstruction of venous outflow (compression of the iliac and renal veins) can cause pain and discomfort due to the activation of nociceptors and cause symptoms such as varicose veins of the lower extremities and genitals (Kasher E. et al., 2023).

Hormonal factors also play a role in the development of venous congestion. The correlation between pelvic congestion syndrome and ovarian activity can be explained by the physiological effects of female sex hormones. Estrogens cause increased secretion of nitric oxide, which leads to increased dilation and weakening of the veins, causing more stress on the valves. Studies show that estrogen levels are significantly higher in women with varicose veins than in those with unaffected vessels. Fluctuations in estrogen levels also affect nociceptive sensitivity. Progesterone has a similar effect and weakens the valves in the veins of the small pelvis. In addition, symptoms may disappear completely after menopause (Bałabuszek K. et al., 2022).

Examination of patients with venous dysfunction

Diagnostic investigation in patients with chronic pelvic pain includes clinical examination, invasive and non-invasive examination methods. Ultrasound examination (US) remains the first-line screening method. Conventional B-mode US allows assessment of pelvic anatomy and exclusion of additional formations as a cause of venous dysfunction, while Doppler imaging measures blood flow parameters. US (transvaginal or transabdominal) allows you to assess not only the diameter of the veins, but also the degree of venous insufficiency and reflux in real time.

Table. Disorders with symptoms similar to pelvic congestion syndrome

Diagnosis of the condition of the veins in the lower extremities is an auxiliary measure that reflects the complex functioning of the venous system. Radiological imaging methods are also used in patients with vascular lesions. Computed tomography (CT) provides cross-sectional images of veins and the precise anatomical location of vessels. Magnetic resonance imaging of the small pelvis can provide excellent image quality and high spatial resolution for the reproduction of anatomical details and vessels of the small pelvis. Contrast-enhanced magnetic resonance angiography provides high sensitivity in the diagnosis of venous insufficiency (Antignani P. L. et al., 2019). Invasive studies of the organs and vessels of the reproductive system include catheter-guided selective phlebography, intravascular ultrasound, and laparoscopic diagnostic methods.

Chronic pelvic pain is associated with adverse cognitive, behavioral, sexual, and emotional consequences, symptoms that indicate dysfunction of various systems, including the reproductive system, lower urinary tract, intestines, pelvic floor, myofascial structures, as well as neurological disorders.

This pathology often requires a joint interdisciplinary approach involving a gynecologist, vascular surgeon, diagnostic and interventional radiologists, urologist, neurologist, psychologist, and psychiatrist, which can sometimes be quite difficult due to significant differences in the interpretation of examination results. Among the factors contributing to the development of chronic pelvic pain, pelvic congestion syndrome accounts for 16 to 31% of cases, ranking second in prevalence after endometriosis. Recognizing pelvic congestion syndrome is tricky because of the variety of clinical signs and symptoms. Plus, a lot of non-venous diseases have similar symptoms (table) (Bałabuszek K. et al., 2022).

Approaches to the treatment of pelvic venous congestion syndrome

Pharmacological treatment of pelvic venous congestion syndrome is limited due to the small number of specialized clinical studies involving this category of patients. Hormone therapy, which suppresses ovarian function, has shown some effectiveness but has been accompanied by numerous side effects. In contrast, venoactive drugs have been shown to be effective in treating the symptoms of venous insufficiency.

Micronized purified flavonoid fraction (MPFF) is a flavonoid-based venoactive drug that effectively reduces pain and discomfort caused by varicose veins in the pelvis and improves venous outflow.

Simsek et al. (2021) studied the effectiveness of MOFF in a standard (1000 mg once daily – study group 1) or double dose (1000 mg twice daily for 1 month, followed by 1000 mg once daily for 1 month – study group 2) in relieving pelvic pain in patients with venous congestion syndrome. The treatment was associated with a significant reduction in pain intensity on a visual analog scale from 3.4 to 1.2 points (p=0.03) when using the standard dose for 2 months and from 7.3 to 0.8 points (p=0.001) when using a double dose for 1 month. Pain relief was achieved on average after 13.7 and 3.1 days in groups 1 and 2, respectively (p=0.0001).

It is important to reduce pain more quickly with a more intensive treatment regimen, as patients with chronic pelvic pain syndrome often use various medications for a long time without any effect. In addition to its significant effect on pelvic pain, MOFF has a beneficial effect on the hemodynamics of the pelvic veins. This was manifested by an increase in blood flow velocity in the internal iliac veins and a decrease in blood stasis in the pelvic venous plexuses, which was confirmed by duplex ultrasound scanning and CT with in vivo labeled erythrocytes. These effects are due to the influence of MOFF on the tonic-elastic properties of the pelvic veins and an increase in their contractile capacity.

Post-marketing studies have shown that the drug Normoven 1000 (manufactured by Kyiv Vitamin Plant JSC) is therapeutically equivalent in terms of efficacy to the original drug in patients with chronic venous insufficiency. The drug contains 1000 mg of MOFF (900 mg of diosmin and 100 mg of hesperidin), which provides angioprotective, capillary-stabilizing, anti-edema, and anti-inflammatory effects.

The use of Normoven 1000 in patients with venous dysfunction has a number of advantages:

• prevents venous stasis and thrombosis;
• increases the tone of the venous wall;
• improves lymphatic drainage;
• normalizes microcirculation.

Studies have shown that strengthening venous tone through MOFF can improve blood circulation in the pelvis in patients with pelvic venous congestion syndrome and alleviate symptoms such as pain and heaviness (Antignani P.L. et al., 2019).

The etiology of pelvic congestion syndrome remains poorly understood and is the result of a combination of factors, including genetic predisposition, anatomical features, hormonal changes, damage to the venous wall, valve dysfunction, and venous dilatation. Hormonal factors play a key role in the development of pelvic venous dysfunction, with the influence of female sex hormones being of paramount importance. It is clear that hemodynamic changes in vein function have a significant impact on the female reproductive system. The limited availability of therapeutic options creates a need to study targeted drugs to improve vein function. Flavonoids, in particular MOFF, have been shown to be effective and safe not only in the treatment of lower limb veins, but also in women with pelvic venous congestion syndrome. The domestic drug Normoven 1000, which contains the active fraction MOFF, has a venotonic and angioprotective effect.

Prepared by Kateryna Pashynska