The prevalence of ovarian varicose veins and varicocele

The prevalence of ovarian varicose veins and varicocele in patients with cancer and/or Venous Thrombosis. Kennedy Gonçalves Pacheco E-mail: kennedy-gp@uol. com. br Celular: (21) 9 9811 -8965

• Because the breast was “held in control” by the ovaries Beatson decided to test the removal of the ovaries in advanced breast cancer in 1896.

• He found that oophorectomy often resulted in improvement for breast cancer patients.

• A half century after Beatson’s discovery, Charles Huggins, a urologist at the University of Chicago, reported dramatic regression of metastatic prostate cancer after the testicles were removed.

• Their work provided a foundation for the modern use of hormone therapy, such as tamoxifen and the aromatase inhibitors, to treat or prevent breast cancer.

• Making the role of germinating glands evident in this pathology.

• Could varicocele in men and ovarian varicose veins in women be associated with cancer? And venous thrombosis?

• Studies show an association between infertility and cancer. • • Tarín JJ 1, García-Pérez MA 2, 3, Hamatani T 4, Cano A 5, 6. Infertility etiologies are genetically and clinically linked with other diseases in single meta-diseases. Gat Y, Bachar GN, Zukerman Z and Gornish M (2004 a) Varicocele: a bilateral disease. Fertil Steril

• A major cause of male infertility is varicocele. • Gat Y, Bachar GN, Zukerman Z and Gornish M (2004 a) Varicocele: a bilateral disease. Fertil Steril

• It is known that varicocele can be associated to male infertility and oxidative stress. • Cozzolino DJ et al. , Varicocele as a progressive lesion: positive effect of varicocele repair.

• The varicocele can change the testicles’ phenotype. • Varicocele-associated pathology mainly includes changes in testicular size, histology, impaired Leydig cell function (steroidogenesis), and spermal abnormality. • Allamaneni S S, Naughton C K, Sharma R K, Thomas A J Jr, Agarwal A, ìIncreased seminal reactive oxygen species levels in patients with varicoceles correlate with varicocele grade but not with testis sizeî, Fertil Steril (2004); 82; (6): pp. 1, 684ñ 1, 686.

Data shows that male reproductive failure may act as a precursor of future andrological malignancies, including testicular or prostate cancer.

Varicocele is associated to Benign Prostatic Hyperplasia.

Varicocele is associated to prostate cancer.

• Klinefelter’s syndrome – hypogonadism with androgen deficiency, high levels of gonadotrophins and semen abnormalities. • Increase the risk of profound venous thrombosis, pulmonary embolism and cancer. • • Campbell WA, Price WH. Venous thromboembolic disease in Klinefelter's syndrome. Clin Genet 19: 275 -280, 1981. Lapecorella M, Marino R, De Pergola G, Scaraggi FA, Speciale V, De Mitrio V. Severe venous thromboembolism in a young man with Klinefelter's syndrome and heterozygosis for both G 20210 A prothrombin and factor V Leiden mutations. Blood Coagul Fibrinolysis. 2003 Jan; 14(1): 95 -8. Stewart, J. A et al. , Thromboembolic disease associated with ovarian stimulation and assisted conception techniques. Hum reprod. , 12, 2167 -2173. Cancer Incidence and mortality in men with klinefelter syndrome: a cohort study. Anthony J et al. , 2005.

Varicose veins in the lower limbs are associated with high levels of: • - Oxidative Stress • - Uncontrolled Angiogenesis • - Endothelial dysfunction • Nicolaides AN, Cardiovascular Disease Educational and Research Trust, European Society of Vascular Surgery, The International Angiology Scientific Activity Congress Organization, International Union of Angiology, Union Internationale de Phlebologie at the Abbaye des Vaux de Cernay: Investigation of chronic venous insufficiency: a consensus statement (France, March 5 -9, 1997). Circulation 2000; 102: E 126–E 163.

• After treatment, oxidative stress levels are lowered and the ulcer is able to heal.

Varicocele in men are associated with High levels of: • • • - Oxidative Stress - Abnormal semen characteristics - DNA fragmentation in sperm - Altered hormone production - And even testicular atrophy. • Chen SS, Huang WJ, Chang LS, Wei YH: Attenuation of oxidative stress after varicocelectomy in subfertile patients with varicocele. J Urol 2008; 179: 639– 642. • Lemack GE, Uzzo RG, Schlegel PN, Goldstein M: Microsurgical repair of the adolescent varicocele. J Urol 1998; 160: 179 -181.

Varicocele is associated to DNA fragmentation which can cause embryological defects and the birth of children with cancer. These are pictures of two of my patients whose parents’ varicocele treated with embolization. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. Greco E 1, et al. , J Androl. 2005 May-Jun; 26(3): 349 -53

• • The treatment of varicocele results in: Improvement in testosterone production Reduced levels oxidative stress Increased fertility • Chen SS, Huang WJ, Chang LS, Wei YH: Attenuation of oxidative stress after varicocelectomy in subfertile patients with varicocele. J Urol 2008; 179: 639– 642.

Varicocele may be confirmed by ultrassound

Varicocelectomy

• Could ovarian varicose veins provoke infertility in women?

Is it possible that the high level of Oxidative Stress disturbs the ovaries?

Does it interfere with the production of oocytes and follicular hormones?

• Two recent studies have shown that oxidative stress (OS) is greater in varicose veins with insufficient valves. • Krzyściak W, Kózka M: Generation of reactive oxygen species by a sufficient, insufficient and varicose vein wall. Acta Biochim Pol 2011; 58: 89 -94. • Karatepe O, Unal O, Ugurlucan M, Kemik A, Karahan S, Aksoy M, Kurtoglu M: The impact of valvular oxidative stress on the development of venous stasis ulcer valvular oxidative stress and venous ulcers. Angiology 2010; 61: 283 -288.

This article suggests that ovarian varicose veins and oxidative stress in the ovaries of female rats could cause infertility.

• Oxidative stress may provoke dysfunction of organs, gene mutation and alterations in angiogenesis. • • Ohura N, Yamamoto K, Ichioka S, Sokabe T, Nakatsuka H, Baba A, Shibata M, Nakatsuka T, Harii K, Wada Y, Kohro T, Kodama T, Ando J: Global analysis of shear stress-responsive genes in vascular endothelial cells. J Atheroscler Thromb 2003; 10: 304 -313. Brown NS, Bicknell R. Hypoxia and oxidative stress in breast cancer. Oxidative stress: its effects on thegrowth, metastatic potential and response to therapy of breast cancer. Breast Cancer Res. 2001; 3: 323327 .

• Treatment of 19 patients with ovarian varicose veins and considered to be infertile, 14 later became pregnant. (Embolization of ovarian varicose veins). • Galkin EV, Grakova LS, Naumova EB: [Roentgeno-endovascular surgery of hypofunctional ovaries in varicosities of the ovarian veins]. Vestn Rentgenol Radiol 1991; 5: 51 -59.

Endometrial and ovarian cancer in idiopathic infertility.

In my study, 80% of the patients with endometriosis had ovarian varicose veins. In my control group, only 26. 1 % had ovarian varicose veins. Article in Press The Prevalence of Ovarian Varices in Patients with Endometriosis Kennedy Gonçalves Pacheco, Maria Raquel Fortes de Oliveira

• We have reported cases of premature ovarian failure associated to ovarian varicose veins. • After treatment through embolization the patients began menstruating again. • Kennedy Gonçalves Pacheco and Raquel Fortes. “Ovarian Varicose Veins may Provoke Premature Ovarian Failure? ” EC Gynaecology 2. 2 (2015): 156 -162.

Could ovarian varicose veins provoke: • Reduction of ovarian reserve? • Occult ovarian insufficiency?

• BRCA 1 gene may also be associated with: • primary occult ovarian insufficiency and • infertility. • Keefe DL, Franco S, Liu L et al: Telomere length predicts embryo fragmentation after in vitro fertilization in women: Toward a telomere theory of reproductive aging in women. Am J Obstet Gynecol 192: 1256 -1260, 2005; discussion 60 -61. • Magli Mc et al. , Incidence of chromosomal abnormalities from a morphologically normal cohort of embryos in poor-prognosis patients. J Assist Reprod Genet 15: 297 -301, 1998.

Is it possible that ovarian varicose veins also provoke? • - Oxidative Stress? • - Alterations in the formation of follicles and oocytes? • - Causing an imbalance in the genetic, hormonal, and immunological composition of the ovaries?

• Could ovarian varicose veins change the phenotype of the ovaries?

• A study shows that 55% of patients with ovarian varicose veins have polycystic ovaries. • Ignacio EA, Dua R, Sarin S, et al. Pelvic congestion syndrome: diagnosis and treatment. Semin Intervent Radiol 2008; 25: 361– 368.

• A change in the phenotype of polycystic ovary syndrome increases the risk of cancer and venous thrombosis. • Ekwutosi M. Okoroh MD. , et al. Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003 -2008. • Tao Zuo, Minghui Zhu and Wenming Xu. Roles of Oxidative stress in polycystic ovary syndrome and cancers.

• Could oxidative stress in ovarian varicose veins cause disturbances in the hypothalamic-pituitary-ovarianaxis?

• Schiffenbauer et al. , showed that loss of ovarian function (which has elevated gonadotropin serum levels) promotes the growth of ovarian epithelial tumors (OETs) in vivo by accelerating angiogenesis. • Schiffenbauer et al. , Loss of ovarian function promotes angiogenesis in human ovarian carcinoma. Proc Natl Acad Sci USA 1997; 94: 13203 -8.

• Ovarian hyperstimulation -> After gonadotropin administration -> may cause venous thromboembolism • Ulug U et al. , Bilateral internal jugular venous thrombosis following successful assisted conception in the absence of ovarian hyperstimulation syndrome. 2003, 15; 109(2): 231 -3.

• What calls one’s attention is the fact that the stimulation of the ovary for purposes of ovulation could bring about complications, such as: Thrombosis in unusual vessels: • • Jugular vein Cerebral vein Retina vein And even in the arteries El Sadek MM, Amer MK, Fahmy M. Acute cerebrovascular accidents with severe ovarian hyperstimulation syndrome. Hum Reprod 1998; 13: 1793 -5. Elford K, Leader A, Wee R, Stys PK. Stroke in ovarian hyperstimulation syndrome in early pregnancy treated with intra-arterial rt-PA. Neurology 2002; 59: 1270 -2.

• Cancer is often associated with venous thrombosis, a phenomenon that was first described by Trousseau in 1865 (Trousseau syndrome), who later diagnosed himself with the same condition. Trousseau A. Phlegmasia alba dolens. Clinique Medicale de l'Hotel-Dieu de Paris. 2 nd ed. Paris, France: The Sydenham Society; 1865. p. 654– 712.

• Retrospective observational study

• I used a sample of 14. 800 patients from my private practice of vascular surgery from April 2012 to June 2015. • I selected 152 patients (1. 02%) 98 with venous thrombosis 54 with cancer

• The method which is used the most to diagnose varicocele and ovarian varicose veins is the ultrasound with vascular Doppler (for not being invasive)

• Ultrassound and phlebography in the diagnosis of varicose veins beside the ovaries.

• There is controversy regarding the minimum diameter of varicose veins next to the ovary (ranging from 4 to 6 mm) • Barros FS, Perez JMG, Zandonade E, Salles-Cunha SX, Monedero JL, Hilel ABS, Menezes AABd, Barros DS: Evaluation of pelvic varicose veins using color Doppler ultrasound: comparison of results obtained with ultrasound of the lower limbs, transvaginal ultrasound, and phlebography. J Vasc Bras 2010; 9: 15– 23. • Kim HS, Malhotra AD, Rowe PC, Lee JM, Venbrux AC: Embolotherapy for pelvic congestion syndrome: long-term results. J Vasc Interv Radiol 2006; 17: 289– 297. • Monedero JL, Ezpeleta SZ, Perrin M: Pelvic congestion syndrome can be treated operatively with good long-term results. Phlebology 2012; 27(Suppl 1): 65– 73. • Ratnam LA, Marsh P, Holdstock JM, Harrison CS, Hussain FF, Whiteley MS, Lopez A. : Pelvic vein embolisation in the management of varicose veins. Cardiovasc Intervent Radiol 2008; 31: 1159 -1164.

• The minimum diameter of varicose veins in varicocele in men is also controversial (ranging from 2 to 3 mm) • Hamm, B. , Fobbe, F. , Sorensen, R. , Felsenberg, D. Varicoceles: Combined sonography and thermography in diagnosis and post therapeutic evaluation. Radiology. 1986; 160: 419– 424. • Rifkin, M. D. , Foy, P. M. , Kurtz, A. B. , Pasto, M. E. , Goldberg, B. B. The role of diagnostic ultrasonography in varicocele evaluation. J Ultrasound Med. 1983; 2: 271– 275. • Wolverson, M. , Houttuin, E. , Heiberg, E. , Sundaram, M. , Gregory, J. High-resolution real-time sonography of scrotal varicocele. AJR Am J Roentgenol. 1983; 141: 775– 779.

• The golden standard is pelvic phlebography. It is, however, invasive. Most times, it is used when the intention is treatment.

OVARIAN VARICOSE VEINS – RENAL CANCER Ultrassound Phlebography

OVARIAN VARICOSE VEINS – Thrombosis of the ovarian vein and pulmonary embolism Ultrassound Phlebography

Ovarian varicose veins- 4 thrombosis and thrombophilia Ultrassound Phlebography

Ovarian varicose veins- Breast cancer Ultrassound Phlebography

Varicocele – Venous thrombosis and leg ulcer Ultrassound Phlebography

Varicocele – Venous thrombosis and psoriasis Ultrassound Phlebography

Psoriasis = uncontrolled angiogenesis: 1 month after treatment (embolization of varicocele)

Do varicose veins next to the ovaries/testicles play a significant role in the uncontrolled angiogenesis and mutagenesis of cancer?

TABLE The result is highly significative.

Our finding of the high prevalence of ovarian varices and varicocele in patients with cancer or venous thrombosis warrants more studies to confirm a new theory that the gonadal varicose veins play an important role in the development of these pathologies.

I would like to extend an invitation to the international community, to join me in engaging in more research related to this subject.

Kennedy Gonçalves Pacheco § Angiologist and Vascular Surgeon § Member of the French society of Phlebology § Contact : +55 21 9811 -8965 / 3350 -2711. § Email: Kennedy-gp@uol. com. br