Transcript The prevalence of ovarian varices in patients with cancer

The prevalence of ovarian varicose
veins and varicocele in patients with
cancer and/or Venous Thrombosis.
Kennedy Gonçalves Pacheco
E-mail: [email protected]
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.
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Tarín JJ1, García-Pérez MA2,3, Hamatani T4, Cano A5,6. Infertility etiologies are genetically and clinically
linked with other diseases in single meta-diseases.
Gat Y, Bachar GN, Zukerman Z and Gornish M (2004a) Varicocele: a bilateral disease. Fertil Steril
• A major cause of male infertility is varicocele.
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Gat Y, Bachar GN, Zukerman Z and Gornish M (2004a) 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.
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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. 1,684ñ1,686.
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.
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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 G20210A 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:E126–E163.
• After treatment, oxidative stress levels are
lowered and the ulcer is able to heal.
Varicocele in men are associated with High levels of:
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- Oxidative Stress
- Abnormal semen characteristics
- DNA fragmentation in sperm
- Altered hormone production
- And even testicular atrophy.
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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.
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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 E1, et al., J
Androl. 2005 May-Jun;26(3):349-53
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The treatment of varicocele results in:
Improvement in testosterone production
Reduced levels oxidative stress
Increased fertility
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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.
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Krzyściak W, Kózka M: Generation of reactive oxygen species by a sufficient, insufficient
and varicose vein wall. Acta Biochim Pol 2011;58:89-94.
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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.
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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).
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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.
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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?
• BRCA1 gene may also be associated with:
• primary occult ovarian insufficiency
and
• infertility.
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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.
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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.
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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.
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Ekwutosi M. Okoroh MD.,et al. Is polycystic ovary syndrome another risk factor for venous
thromboembolism? United States, 2003-2008.
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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.
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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
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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:
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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. 2nd 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)
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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.
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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.
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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.
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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)
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Hamm, B., Fobbe, F., Sorensen, R., Felsenberg, D. Varicoceles: Combined sonography and thermography in
diagnosis and post therapeutic evaluation. Radiology. 1986;160:419–424.
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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.
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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: [email protected]