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Lipedema fat and signs and symptoms of illness, increase with advancing stageARCHIVES OF MEDICINE
Lipedema Fat and Signs and Karen L. Herbst1,
Symptoms of Illness, Increase Liza Mirkovskaya1,
with Advancing Stage Aditi Bharhagava1,
Charisse Hanne T. Te2
1 Department of Medicine, University of California, San Diego, CA, USA 2 Department of Medicine, University of Background: Lipedema is a poorly known disorder of painful subcutaneous adi-
Arizona, Tucson, AZ, USA pose tissue (SAT) likely affecting millions of women worldwide. Stage 1 lipedema has smooth skin with increased underlying fat, Stage 2 has indentations and nod- ules, and Stage 3 has large extrusions of skin and SAT. Women with lipedema have more SAT below the waist. As this gynoid fat is known to be cardioprotective, we Corresponding Author: Karen L. Herbst
aimed to determine if health declined with increasing stage and extent of lipede- Department of Medicine, Division of Endocrinology, University of Arizona, 3950 Methods and Findings: Chart review from June 2012 to February 2013 at a ter-
South Country Club Drive, Suite 200, Room tiary academic center. Fifty women and one man were included in consecutive 2221, Tucson, Arizona, USA order. Fat was assessed in 29 areas for lipomas, size of the depot, and presence of lipedema fat. Pain was assessed by a numerical pain scale. Average age of patients was 50 ± 13 y; average body mass index was 38 ± 12 kg/m2. Median age of devel- opment of lipedema was 20 y. Pain occurred daily in 89.7%. None of the patients with Stage 1 lipedema had diabetes, hypertension or dyslipidemia. The amount of lipedema fat differed significantly between Stages of lipedema (p=0.003), with Stage 3 having significantly more. There was no difference in fat depot size or number of lipomas amongst Stages. Only one of 51 patients had type 2 diabetes. There was an increase in shortness of breath, palpitations, urination, and numb- ness in Stage 3.
Conclusions: Lipedema fat can develop in any SAT location and increases in asso-
ciation with increasing signs and symptoms of systemic illness.
Keywords: Lipedema, lipoedema, lymphedema, lipolymphedema, spheroids
underlying SAT similar to a mattress  containing larger mounds of SAT that grow as non-encapsulated masses, lipomas and Lipedema (lipoedema in Europe) meaning fluid or swelling in fat angiolipomas; Stage 3 where large extrusions of tissue (skin is a painful disorder involving subcutaneous adipose tissue (SAT). and SAT) cause gross deformations especially on the thighs and Lipedema was first named in the literature in 1940 by Drs. Allen around the knees. Lymphedema, where lymph fluid develops and Hines as a condition occurring almost exclusively in women dependently on the feet and hands increasing cranially due who suffer from enlargement of fat tissue of the lower extremities to dysfunctional lymphatics, can develop during any stage of and buttocks ; older literature also contains descriptions of lipedema, and is called lipolymphedema or Stage 4 lipedema. women with lipedema [2,3]. In more recent literature, lipedema Lipedema therefore is a pre-lymphedema condition; though not is described as a bilateral condition that does not affect the hands everyone with lipedema will go on to develop lymphedema.
or feet  with a disproportion between a smaller upper body The authors found in clinical practice that lipedema fat tissue was and a "voluminous" lower body .
found more extensively on the body than is currently described There are three stages of lipedema that refer primarily to changes in the literature. In addition, women with stage 3 lipedema in the skin [6,7]: appeared to have greater and more serious complaints than women with earlier stages of lipedema. The goal of this report Stage 1 in which there is a normal skin surface with enlarged was to gain a greater understanding of the extent of lipedema hypodermal SAT; Stage 2 with indentations of the skin and tissue on the body in all stages, and to determine if a later stage Copyright iMedPub This article is available from: www.archivesofmedicine.com
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of lipedema was associated with a greater number of signs and waist, and down as far as the medial and lateral malleoli and that symptoms suggestive of a serious decline in health.
upper arms can be affected . Cornely stated in a recent paper that the arms are affected in 80% of women with lipedema . Beninson et al. mentioned that trunk and upper extremities are Protocol: Chart review from a subspecialty Endocrinology clinic usually normal in patients affected with lipedema . Dietzel et
at the University of California, San Diego (UCSD), to which al. found the disproportion between the upper and lower body patients self-referred or were formally referred for evaluation was lost when obesity was present with lipedema . Combined, and recommendations for treatment, from June 2012 to these data in the absence of obesity provide a picture of a woman February 2013. Patients were included in consecutive order if with lipedema whose lipedema SAT can extend as high as her they had or were given a diagnosis of lipedema, had a charted lower abdomen (up to the umbilicus), primarily located on her physical exam, and a complete review of systems. This research legs, and upper arms, but not her hands, feet or trunk.
was considered exempt by the UCSD Human Research and Population characteristics: The majority of the patients in this
Protection Program. study had stage 2 lipedema (Table 1) including a single man (age
Fat assessment: Lipedema fat has been astutely described 25 y). Two women with stage 2 lipedema had lipolymphedema
as feeling like small firm beans in a bag . These small, (6%) and five women with stage 3 lipedema had lipolymphedema approximately 5 x 5 - 10 x 10 mm "beans", are rounded fat (38.5%), also known as stage 4 lipedema. Body mass index lobules, distinct from one another yet closely packed together, values were available for 46 patients. Four women (8.7%) had that resemble spheroids, the buck-shot sized, hard, calcified, normal BMI (<25 kg/m2), three with stage 1 and one with stage 2 lipedema. Seven women (15.2%) were overweight (BMI ≥ 25 subcutaneous nodules resulting from fat necrosis present in ≤ 30 kg/m2, one with stage 2 lipedema and the remainder with connective tissue disorders . In this report, fat on the entire stage 3 lipedema; in the latter group, one had stage 4 lipedema. body was assessed qualitatively by visualization as increased, The remainder of the patients, including the man, were obese normal or decreased, and by hands-on exam in 29 areas of the (76.1%), six of which had stage 4 lipedema. body from head to dorsal foot examining for spheroids and lipomas. The breasts were not included in the palpation due to Data on onset of lipedema was available for 41 patients. The the fibrocystic nature of breast tissue and inability to accurately median and average age of onset was 20 y and 24.3 ± 2.2 y, determine the presence of lipedema tissue. When the beans in respectively. Twenty two (53.7%) stated they developed lipedema a bag feel to the fat was encountered by palpation, the fat was by the age of 20 y, eighteen (43.9%)stated they developed recorded as containing spheroids. The fat on the head can be lipedema after the age of 20 y, 9.8% after the age of 40 y and only increased with a sponge-like feel in women with later stages of two after the age of 50 years, specifically at 54 y (stage 2) and 63 lipedema and was included in the spheroid analyses.
y (stage 2 and 4). Pain and joints: Determined by numeric scale as average, high 40% of participants never had children. Sixteen women were
and low pain, with zero being no pain and ten being the worst multiparous and of these women, two had stage 3 lipedema.
pain ever. Hypermobile joints were assess using the Beighton Past Medical and Surgical History: Over 30% of patients had
hypermobility score .
abdominal or pelvic procedures (Table 1). These surgeries included
Statistics: A one-way between-subjects ANOVA was used to test cholecystectomy, loop electrosurgical excision procedure (LEEP),
for the difference in number of areas with spheroids, size of the tubal ligation, panniculectomy, Cesarean section, uterine fibroid fat depot and the number of lipomas based on the patient's tumor removal, repeated dilation and curettage (D&C) of the lipedema stage. When appropriate, Tukey HSD post-hoc cervix, ovarian cyst removal, or ovarian reconstruction. Over 30% analyses were used. A Pearson Chi-Square analysis was used to of the patients had arthritis, dyslipidemia or hypertension (Table
test for the difference in the number of Symptoms in Patient's 1). None of the patients with stage 1 lipedema had hypertension,
Past Medical History and Review of Systems (SPSS, International dyslipidemia or diabetes. Additional past history found in <30% Business Machines Corporations (IBM; Armonk, NY).
of patients included hypothyroidism (27 ± 0.5%), varicose veins, asthma or hysterectomy (21 ± 0.4% each), fibromyalgia or bariatric surgery (13 ± 0.3% each), and endometriosis (10 Literature review: In a review of 94 articles found under the ± 0.3%). Less than 10% of the patients had diabetes (Table 1),
search term "lipedema/lipoedema" in PubMed in March polycystic ovarian syndrome or gluten allergy (6.3 ± 0.2% each), 2015, 65 were available with full-text for review, and 49 were costochondritis or narcolepsy (4.2 ± 0.2% each), or a factor available in English. This review focused on articles in English V Leiden mutation (2.1 ± 0.1%). Of the patients with diabetes, to avoid mistakes in the translation of articles on computer- one woman with stage 2 lipedema had type 2 diabetes and one generated translators. Out of the 42 articles on lipedema, 8 did patient had type 1 diabetes. Additionally, three patients had a not mention the distribution of lipedema tissue. The majority history of gestational diabetes and two had a history of or had of the remaining articles described lipedema fat as occurring current impaired glucose tolerance for a total of 6 ± 0.3% with almost exclusively on the lower extremities, with occasional insulin resistance or diabetes in their current or past history. The involvement of the buttocks and hips . Fife et al. specifically single male had secondary hypogonadism only.
mentioned that lipedema can spread as far up as the lower Pain and joints: Data for pain was not available for twelve
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patients. Four patients with lipedema denied having any pain of patients in stage 1, 2 and 3 that had a Beighton score of 5 or (10.3%) while the remainder (89.7%) had daily pain (Figure 1). Of more was 40%, 54% and 50%, respectively. There was also no
the patients that had no pain, one had stage 1, two had stage 2, correlation between pain scores and Beighton scores (data not and one had stage 2 with lipolymphedema. A majority of patients shown).
had pain in the joints (57 ± 0.5%), fat (49 ± 0.5%), back (44 ± 0.5%), Location and type of fat: Fat was noted on physical exam as: 1)
legs (39 ± 0.5%) and muscle (37 ± 0.5%). Pain was also noted in Visibly increased in size (amount) from normal; 2) Palpable as the head (25 ± 0.4%), arms (25 ± 0.4%), feet (23 ± 0.4%), stomach small firm spheroids ; or 3) Containing lipomas. These three (16 ± 0.4%), eyes (14 ± 0.4%), and ribs (14 ± 0.4%). The man with types of fat were compared across the three groups of patients lipedema had an average daily pain of 5, with highest pain a 7 and (stages 1, 2, and 3 lipedema). Out of twenty-nine areas assessed lowest a 2 on a daily basis in his eyes, muscles and joints. There for fat size, there was no significant difference (P=0.7) in the was a trend to difference between the groups in the lowest level average number of enlarged fat depots between stage 1 (3 ± 2.6), of daily pain (P=0.07), but not in the highest daily pain (P=0.88) stage 2 (3.7 ± 0.5) and stage 3 lipedema (3.9 ± 0.8). No patient or average daily pain (P=0.18). The average Beighton score for had fat atrophy in any area. hypermobile joints among all patients was 4.2 ± 0.5. There was no difference in Beighton scores between groups; the percentage The amount of lipedema tissue containing spheroids differed significantly across the three groups of patients, F (2, 48) = 6.57 Table 1. Population characteristics, demographics and medical history.
(p = 0.003). Tukey post-hoc comparisons of the three groups indicated that the amount of spheroids increased by stage (Figure
2), and was significantly greater in people with stage 3 (M = 19.31,
SD = 3.38) compared to stage 1 (M =13.80, SD = 4.44; P<0.05) and stage 3 compared to stage 2 (M =16.12, SD = 3.07; P=0.008; Figure
2). There was not a significant difference in extent of tissue with
spheroids in patients with stage 1 compared to stage 2 lipedema. The fat depots in which spheroids were found most commonly Average ± sem
(>50%) included the anterior and dorsal upper and lower arms, ribcage, abdomen, pelvis, subscapular area on the back, flanks, buttocks, front and back of the thighs, the medial knee, popliteal, posterior leg, malleolar, and anterior foot (Figure 3). The sites
in which patients had spheroids <50% of the time included the Age lipedema started (years) cranium, parotid, submandibular, posterior neck, dorsocervical Number of children area, upper chest, hand, and the dorsal foot (boxes, Figure 3);
Past Medical History
Percent ± sem
none of the women with stage 1 lipedema had spheroids in these Abdominal or pelvic surgery areas. The cubital, anterior forearm, abdomen, thighs, medial knee, popliteal and posterior leg had spheroids 100% of the time in women with stage 1 lipedema. None of the patients with stage 2 lipedema had spheroids in the posterior neck or dorsocervical area; the cubital and medial knee areas contained spheroids in Average, highest, and lowest daily pain scores Figure 1 in patients with lipedema.Pain scores were
Figure 2 Average (± sem) number of 29 areas of the
chosen by patients on a scale from 0-10, with 10 body affected with lipedema fat tissue in described as the worst pain ever, and zero as no patients with stage 1, 2, and 3 lipedema. pain.Data are average values ± sem.
P-values as shown.
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Caricature of a woman with stage 3 lipedema. Percentages denote the number of combined patients with stage 1, 2 and 3 Figure 3 lipedema fat in the stated area. Boxes outline areas affected <50% of the time in all patients and suggest a disproportion in
lipedema fat between the upper and lower body. Asterisks denote areas affected with lipedema fat in 100% of patients.
100% of patients in all stages. There were no areas of examined was experienced by 1 person with stage 1 (25 ± 0.5%), seven fat that did not have spheroids in at least one (cranium), two with stage 2 (22.6 ± 16%), and eleven with stage 3 lipedema (parotid, submandibular, posterior neck, dorsocervical, dorsal (36.4 ± 25%). Other notable signs and symptoms that were foot), or more patients with stage 3 lipedema. Patients with stage more frequent in patients with stage 2 and 3 lipedema included 3 lipedema had spheroids in the cubital, anterior and posterior obstructive sleep apnea, blood clot, nausea, constipation, higher forearms, abdomen, flanks, buttocks, thighs, medial knee, and body temperature, flu-like symptoms, and burning pain of the posterior leg 100% of the time. Hands were affected in 21% of skin (Table 2). Signs and symptoms that occurred in <50% of all
patients with stage 2 and 31% of patients with stage 3 lipedema. patients in this study included asymmetry of fat on the left or The anterior chest was affected in 40%, 36%, and 38% of patients right side, unexplained weight loss, lumps in neck fat, difficulty with stage 1, 2, and 3 lipedema, respectively.
swallowing, blurry vision, neck feels swollen, chest pain, burning pain, scalp or other lesions, thirsty all the time, tremors, vomiting, There was no significant difference (P=0.4) in the average number thrombophlebitis, visible veins on arms, tick bite, chronic of lipomas on the body in stage 1 (0.8 ± 0.5), stage 2 (0.9 ± 0.2) sinusitis, warts, myoclonus, dry eyes, dry mouth, vertigo, hearing and stage 3 (0.5 ± 0.2). The number of lipomas in each patient in loss, frequent congestion, depression, and anxiety.
each stage varied between 0-3.
Signs and symptoms: Patients were asked to fill out a questionnaire Discussion
listing 66 items as part of a review of systems prior to their clinical Lipedema is a SAT disorder found primarily in women. The visit. Eighteen signs and symptoms from the questionnaire were prevalence of lipedema has been estimated to affect up to 11% positive in ≥ 50% of the patients with stage 1 lipedema (Table and possibly up to 39% of the female population [17,18]. Using the
2). Unexplained weight gain and muscle weakness were found lower prevalence estimate, over 16 million women in the United
in ≥ 50% of the patients with stage 2 and 3 lipedema, but not States may be affected with lipedema. Lipedema developed in in any patient with stage 1 lipedema. Palpitations, hair loss, patients in our study around the age of 20 y. In the literature, frequent urination, numbness, and shortness of breath were the upper age limit for pubertal changes in the body is 17 y  present exclusively in ≥ 50% of the patients with stage 3 lipedema therefore it is likely that lipedema develops during puberty in a (i.e., not in any patients with stage 1 or 2 lipedema). Cellulitis majority of patients with lipedema. We were not able to address This article is available from: www.archivesofmedicine.com
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Table 2. Signs and symptoms in patients with lipedema (% ± se).
Sign or Symptom
Signs, symptoms in ≥50% of patients with stage 1 lipedema
Low body temperature Difficulty sleeping Poor concentration Visible veins on legs Weigh more at night Signs, symptoms exclusively in ≥ 50% patients with stage 2 and 3 lipedema
Unexplained weight gain Signs, symptoms exclusively in ≥ 50% patients with stage 3 lipedema
Shortness of breath Frequent urination Additional signs and symptoms that increased with stage
Flu-like symptoms High body temperature Obstructive sleep apnea *P<0.001 vs. stage 1, 2 **P<0.05 vs. stage 1 †P<0.05 vs. stage 1, 2 whether lipedema commenced or was affected by childbirth and/ only a small percent of patients with stage 2 and 3 lipedema. In or menopause.
agreement with Cornely , in this study, the dorsal forearm had A review of the literature on lipedema suggests: 1) that lipedema lipedema fat in 80% of patients, and up to 90% of patients had SAT is generally accepted to be located from the ankle up to the lipedema fat on the anterior arm. The number of areas affected lower abdomen and on the upper arms; and 2) that there is a by lipedema fat increased with a higher lipedema stage. In this disproportion between the greater size of the body below the study, the level of disproportion of lipedema fat was higher on waist compared to above the waist, unless obesity is present, the body (up to the axillary area) than previously described (up to and the disproportion is lost . This study of fifty women and the waist). If we set a limit that at least 75% of patients must have a man who presented to a single clinic in an academic setting lipedema fat in an area of the body to be considered as "generally demonstrates that lipedema fat can be found on the body from affected", then lipedema fat can extend from the posterior leg up the cranium (top of the head) down to the underside (dorsal and including to the superior aspect of the axillary crease. side) of the foot with the majority of lipedema fat between the Data from this study suggests that the disproportion of fat on lower axillary region and the ankle; the head and foot were affected in compared to upper body presented in the literature primarily Copyright iMedPub ARCHIVES OF MEDICINE
refers to women with stage 1 and 2 lipedema, in which lipedema major concern resulting from the review of systems in this study fat is not present on the upper body in the majority. Women with was the increase in shortness of breath, palpitations, urination, lipedema are under-diagnosed by healthcare providers who do and numbness in patients with stage 3 lipedema. We hypothesize not compare upper body to lower body fat. It is likely that women that these symptoms suggest excess fluid accumulation in the with stage 3 lipedema are confused more often as having lifestyle- body as pre-lymph or lymph fluid. Indeed, edema and cellulitis induced obesity  as the lipedema fat develops globally and increased with stage of lipedema in this study consistent with this the disproportion diminishes. In stage 3 lipedema, lipedema SAT hypothesis. Women with stage 3 lipedema were also more likely continues to progress to include more areas of the body, and in to have obstructive sleep apnea, nausea, constipation and flu- this stage there may be greater areas of lipedema fat induced by like symptoms. These data suggest that the metabolic protection the development of lipedema secondarily through retention of of the lipedema fat wanes in stage 3 lipedema as the lipedema lymph, as it is well-known that lymph makes fat grow . This fat spreads globally on the body and patients develop signs of area deserves additional research to help patients with lipedema systemic illness. The only known treatment to reduce lipedema and to shed light on changes in fat in lifestyle-induced obesity. fat at this time is excision by lymph-sparing liposuction, a Body composition by dual X-ray absorptiometry scans would treatment for lipedema established in Germany for over 20 years have been helpful in this study to examine the disproportion of [24-26]. Furthering our understanding of the pathophysiology of fat in the different stages of lipedema with greater accuracy as lipedema and medical treatments for reducing lipedema fat are has been published previously . A larger group of patients needed so we are not relying solely on surgical management of with stage 1 lipedema would have also improved comparisons lipedema fat.
amongst the groups.
Hypermobility is not a condition reported in association with Lipedema fat can be distinguished from lifestyle-induced fat by lipedema but in this report, 50% of women with lipedema had palpating spheroids in the fat and in the majority, by pain in the a positive Beighton score ( ≥ 5) suggesting that they may also SAT and/or tenderness on palpation of SAT in areas of spheroids. have the common disorder known as Ehlers Danlos syndrome Most healthcare providers have limited time with patients hypermobility type (EDS-HT) formerly type III) . Pain is a therefore if lipedema is suspected, a focused examination of the common component of EDS-HT and females are functionally cubital and medial knee SAT areas should reveal the presence of affected to a greater extent than males and therefore this lipedema fat as these areas contained spheroids in 100% of the association should be further investigated. patients in our study. Healthcare providers that diagnose patients Venous disease is known to occur in women with lipedema . with lipedema can use International Classification of Diseases The data in this study demonstrated that as the stage of lipedema (ICD) codes specific for "Other lymphedema", ICD-9 457.1, or increased, visible veins decreased. Interestingly, venous blood 272.8 for "other disorders of lipoid metabolism" until lipedema is clots were only present in women with stage 3 lipedema. These recognized by our healthcare system. data suggest a masking of underlying venous disease by excess The stages of lipedema are primarily described in the literature lipedema fat. The development of lymphedema in a patient with with reference to the skin with smooth skin and an enlarged lipedema should prompt not only a reassessment by a manual hypodermis in stage 1, indentations in the skin in stage 2, and lymphatic drainage therapist, but also evaluation for venous lobulations of the skin in stage 3. Data from this study suggest disease by a vascular surgeon, consideration for a sleep study for that the stages of lipedema should refer not only to the quality evaluation of obstructive sleep apnea, and an echocardiogram to of the skin and lipedema tissue, but also that a greater quantity assess for heart failure.
of the body SAT area is affected as the lipedema stage increases; The single man was included in our study to serve as a reminder stating a percent of the body that is affected may be helpful. The that men can also develop lipedema . Men who develop presence of lipolymphedema also increases with progression lipedema tend to be hypogonadal as our patient, have a history from stage 1 to 2 and 3.
of hypogonadal symptoms and signs such as gynecomastia, Lipomas were not found in a large number of women with or have liver disease  resulting in elevated estrogen levels. lipedema but they were present in patients with every stage. In the hypogonadal state in a man, the ratio of testosterone to Better imaging of lipomas by magnetic resonance imaging using estradiol (an estrogen) is altered, and estradiol plays a greater proton-density fat saturated sequences  would provide a role in tissues that have sex hormone receptors such as SAT. much better assessment of lipomas in lipedema.
Lipedema occurs primarily in women suggesting that estrogen plays a pivotal role in the development of lipedema SAT. Men There was no past history that clearly appeared to be associated with higher effective levels of estrogen may be at greater risk for with lipedema. What was striking in this population was the developing lipedema fat. very low incidence of type 2 diabetes (2%). This low prevalence suggests that lipedema fat is not insulin resistant fat, or that This study was performed at a tertiary referral center that was the patients were protected from diabetes in some other available to people living in the local area and to those who can manner. As lipedema fat in earlier stages is in a purely gynoid travel. Patients with lipedema who were too ill to travel or who distribution (hips, buttocks and thighs), and gynoid fat confers were financially unable to travel would be under-represented in lower cardiovascular risk , lipedema fat may also confer less this study.
cardiovascular risk in stage 1 and 2 and possibly also in stage 3. A In conclusion, lipedema is a common disorder likely present in This article is available from: www.archivesofmedicine.com
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millions of women all over the world. Lipedema fat can affect stage 3 lipedema develop signs and symptoms associated with any area of SAT, but is found more often in SAT at or below the increased cardiovascular risk suggesting the need to evaluate axillary area and above the ankle. Obesity increases with stage of for underlying conditions such as venous disease or obstructive lipedema but overall, lipedema SAT confers a disproportionately sleep apnea in patients with lipedema prior to but especially after larger lower body. The presence or absence of lipedema fat can diagnosis of stage 3. Studying lipedema and lipolymphedema can be quickly assessed around the cubit nodes or the medial knee, help millions of women, and provide a better understanding of areas affected in 100% of patients in this study. Women with lymphedema that develops secondary to obesity . Copyright iMedPub ARCHIVES OF MEDICINE
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LEY Nº 18.045 (1) LEY DE MERCADO DE VALORES Objetivos de la ley, fiscalización y definiciones Artículo 1°.- A las disposiciones de la presente ley queda sometida la oferta pública de valores y sus respectivos mercados e intermediarios, los que comprenden las bolsas de valores, los corredores de bolsa y los agentes de valores; las sociedades anónimas abiertas; los emisores e instrumentos de oferta pública y los mercados secundarios de dichos valores dentro y fuera de las bolsas, aplicándose este cuerpo legal a todas aquellas transacciones de valores que tengan su origen en ofertas públicas de los mismos o que se efectúen con intermediación por parte de corredores o agentes de valores.