UTILITY OF AN ORAL PRESENTATION OF HCG (HUMAN CHORIOGONADOTROPIN) FOR THE MANAGEMENT OF OBESITY:A DOUBLE-BLIND STUDY
deal too much with the negative, with what is wrong. Why not try and
Oscar Belluscio* M.D,
Female obese volunteers participating in a double blind study,
and submitted to the administration of an oral presentation of hCG
(Human Choriogonadotropin) plus a VLCD (Very Low Calorie Diet),
decreased specific body circumferences and skinfold thickness from
conspicuous body areas more efficiently than Placebo+VLCD -treated
KEYWORDS: Gonadotropin(s), Chorionic; Obesity; Adipose tissue metabolism; fat ; overweight; beta-endorphin; lypolisis; lipogenesis.
Quite few substances have been so neglected and misunderstood regarding its potential therapeutic actions as hCG, the acronym for Human Chorionic Gonadotropin.
First discovered by Ascheim and Zondek as back as 1927 in the urine from pregnant women (2), thousands of articles were published regarding its action on gonads, but comparatively quite a few investigated its vast therapeutics potentialities, encompassing Kaposi sarcoma (33), asthma (63,65), psychoses (22,23), artheriopaties (14), thalassemia (7,19,56), osteopenia (56), glaucoma (53).
hCG is the glycoproteic hormone normally secreted by trophoblastic cells of the placenta during pregnancy (66). It consists of two dissimilar, separately, but most presumably coordinately translated chains, called the alpha and beta subunits. (12,26,47,27,18,30)
The three pituitary hormones LH (Luteinising Hormone), FSH (Follicle Stimulating Hormone) and TSH (Thyroid Stimulating Hormone) are closely related to hCG in that all fours are glycosilated and have a dimeric structure comprising the alpha and beta chains as well. (31,35,79)
The aminoacid sequence of alpha chain of all four human glycoproteic hormones is nearly identical. The aminoacid sequence of the Beta subunits differs and account for by the unique immunological and biological activities of each glycoproteic hormone (63). Beta hCG contains a carboxylic residue of 30 aminoacids characteristic to hCG (11,52)
Its denomination (Human Chorionic Gonadotropin) dates back from the early days, when it was found hCG rendered mature the infantile sex glands in experimentation animals (Gonadotropin) and it was secreted by the placentary chorion (Chorionic) (2,91).
However, recent data suggest both terms can be misleading: normal human tissues from non-pregnant subjects (88,74,48,86,87), trophoblastic and non-trophoblastic tumors (33,6,90), bacteria (49), and plants (46,69) express hCG or a hCG-like substance.
The first report on hCG and obesity was published back as 1954 in
The Lancet, by a British born physician, graduated in Germany, Dr.
A.T.W. Simeons (70). Dr. Simeons was born in London in 1900 and
graduated in medicine at the University of Heidelberg. After further
studies in Germany and Switzerland he moved to Dresden where he was
appointed to a large surgical Hospital.
After its publication, hCG was advocated for several years as an useful approach to obesity. The pendulum of its popularity swinged back and forth until a serial of studies (1,3,8,17,36) but three (3,25,80) concluded hCG was of no use to manage the disease
According to basic pharmacological postulates, the administration route may influence the biological activity of a drug. All previous studies were performed with a hCG preparation administered by injections. One of the authors of this study (DB) theorized that an increase in dose and a shifting in hCG administration to a sublingual-enteral route may modify the pharmacological activity of hCG.
The purpose of this study was to assess the utility of an oral presentation hCG for the management of obesity.
The study design was of the double-blind type: neither
treating physician nor patient knowing who was receiving hCG, or an inert
substance (placebo). Female patients for the study were selected, since
the clinic where the study was performed specializes in the diagnosis and
treatment of gynecologic disorders.
We required selected volunteers to meet the following criteria: being at least 25 % BMI (Body Mass Index) overweight, and in general healthy condition. If taking medication for obesity, such as anorectics or amphetamines, they should discontinue the medication at least one month prior the initiation of the study.
No teenagers and patients over 75 y.o were admitted to the study. No patients with severe and/or uncontrolled clinical diseases (cancer, IDDM, heart attacks, infarcts sequelae) were accepted. After applying the inclusion/exclusion criteria, we counted on 70 subjects to divide in treatment groups.
Patients were Caucasic, ages ranging from 23 to 73 y.o (group P: 41 ± 13; group G1: 42 ± 12; group G2: 41 ± 14), a range of heights of 1,62 cm. to 1,81 cm., and overweight ranging from 25 to 49,9 on BMI Tables.
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The same Very-Low-Calorie-Diet (VLCD), specific and detailed, was prescribed to all groups.
Volunteers assisted twice weekly at the clinic to be controlled and weighed. The following evaluations were completed once a week:
III. Skinfold thickness. Using a Lange Skinfold Caliper (Cambridge Scientific Industries, Cambridge, Maryland), the following folds were examined:
impedance. Using Tetrapolar Bioelectrical Impedance (TBI) with a body fat analyzer
Maltron, model BF-905 (Maltron International
Ltd., Rayleigh, Essex).
Variables were splitted as follows for a better data processing and statistical results presentation:
· Category I, BW plus four bioelectrical impedance records (FW, LW, WW and CAL),
· Category II, eight anthropometrical measurements (corporal circumferences WRT, BRE, WAT, ABD, HIP, THI, ROT and ANK).
· Category III, nine skinfold assessments (TRI, AXA, SCA (I), TOR, ILI, UMB(u), UMB(l), THI, ROT) (see long names and definitions for the studied variables at the beginning of this section).
Each set was analyzed with a two-way multivariate analysis of variance (MANOVA), comparing the obtained Wilks-lambda' F with the corresponding critical value.
TREATMENT (VLCD diet plus group-specific pharmacological intervention) was considered the between-subject factor with three levels (P, G1, G2), and WEEK of clinicometric control served as an additional within-subject factor with six levels: weeks 0 to 5.
To estimate how the differences between treatment' groups depended on the trial time elapsed since week zero (comparison of pattern trend changes in function of treatment time) we obtained the MANOVA result for the effect of the INTERACTION (also displayed in the text as TREATMENT x WEEK).
Moreover, to prevent any possible influence of acute effects specifically associated to any VLCD program in the adaptation phase (first 5-7 days), we additionally evaluated with separate MANOVA analyses the differences between groups and within subjects in the course of the last four treatment's weeks.
After obtaining a statistically significant multivariate test for a particular main effect or interaction, we further examined the univariate F tests for each dependent variable. When parameters from these tests displayed significant modifications, data were further analyzed to ascertain which group (P, G1 or G2) was the responsible for the previous p values obtained.
We also compared data basal values from each group against those obtained in subsequent weeks (e.g., records of week 0 against week 1, thereafter against week 2, and so on). These pairwise comparisons were statistically assessed applying a post hoc Scheffé F tests.
Questionnaire responses were converted into percentages and submitted to a chi-square (2c) test to compare between-groups and within-groups (pairing off final vs. initial data) statistic results.
To attenuate the natural source of within-subject variation, inherent to all assessments of subjective symptoms, we averaged data results from identical questionnaires completed weekly during the initial first two study weeks. Thus, we obtained a more precise "initial questionnaire" (avoiding the potential "adaptation effect" common to any VLCD regime in the first treatment week).
To obtain the final mood behavior results over the last two treatment weeks, they were averaged using the same schema as detailed before. Criteria for significance was p<0.05. Statistica 4.2 (from StatSoft, Inc.) for Windows software was used in all processing.
1, 2, 3
,4 and 5)
Concerning hCG and its utility for the management of obesity, this study introduces two new aspects, and adds new data for a third:
I) This is the first report assessing variables not included in
previous reports (38,51,68,89);
These assertions will be separately discussed:
I) Skinfold thickness (SKF) and Tetrapolar Bioelectric Impedance (TBI) records.
Both approaches have been extensively discussed in the literature. It was shown that the correlation between the values obtained with the two methods to be linear and highly significant for both sexes (42,81,27).
There is general agreement that skinfolds calipers are particularly useful in the clinical setting (56,82,16,76,10,65, 9,15,75), particularly in view of the fact that measurement of subcutaneous body fat at different body sites is becoming increasingly important for the characterization of risk of certain disease states (55).
When comparing skinfolds assessments to body circumference estimates, despite some data suggest that the latter approach appears to be more sensitive in the determination of subcutaneous body fat (53), this procedure is in our opinion subjected to clinical variables (bloating syndrome after a meal, premenstrual water retention, etc.) that may affect negatively on the final estimates results.
Also, when comparing SKF to body contour assessments, some data suggest that the pattern of fat thickness body distribution measured over several specific sites by one method of measurement is unlikely to be duplicated by of the other method on the same individual (40,41).
Adipose tissue patterns show great variability, showing the importance of using skinfold caliper readings from a variety of different anatomic sites including upper limbs, lower limbs and trunk (30,65).
According to the above conclusions from several authors (72,13,60, 25,73,62), we would like to suggest that former studies on hCG and obesity lacked of sufficient data to estimate accurately modifications of adipose tissue distribution in tested volunteers. Consequently we designed the study to assess as many as possible variables.
As far as our study concerns, we subjected each volunteer
enrolled in the trial to four bioelectrical impedance, eight
anthropometrical plus nine SKF evaluations. Performing this multiple
site determinations, our results show that specific SKF are highly
responsive to hCG pharmacological intervention (upper and lower
II) Oral hCG is an valuable alternative administration route
No data appear on the scientific literature regarding an oral administration of hCG in humans. But results from this study suggests hCG may be used by the sublingual-enteral route. Despite plasmatic ß-hCG remained undetectable both in Placebo and hCG groups throughout the study, an oral administration of hCG proved to possess therapeutic activity.
Since commercial preparations of hCG contains ß-endorphin (see below), it may be tempting to hypothesize that this pentapeptide might account for the pharmacological activity observed on mood stability during the Protocol.
III) Volunteers treated with hCG coped better with daily irritating situations.
As can be seen on Figure 5, hCG-treated groups handled better their irritability, their mood at home, and were less prone to episodes of extreme nervousness capable of provoking violent discussions . Several reports proposed hCG might be used for the treatment of psychoses or neurosis (29,61,24). Our study appears to corroborate these proposals.
To conclude, this study poses several still unanswered questions:
1. hCG plasmatic levels. We have tested all volunteers, screening for the b-hCG in plasma. Concentrations were undetectable in all cases.
Therefore, which hCG fraction is responsible for the pharmacological activity observed in our study? hCG molecular size (alpha chain -14,500 KD; beta chain -22,200 KD) makes highly improbable that the entire molecule has been absorbed. Our hypothesis is that only a fraction of the entire hCG molecule is absorbed through this administration route .
2. hCG and lipid metabolism. We do not know precisely how hCG acts on adipose tissue metabolism. However, some reports (32,84,85,83 ) suggest hCG possesses a metabolic activity on adipose tissue (i.e. decrease lipogenesis). These actions are not directly exerted on adipocytes, since fat cell membranes have no receptors for hCG (32).
3. hCG and mood. A stable mood and lack of attrition characterized the hCG-treated group.
It is well known that VLCD's are associated with mood changes, particularly attrition (78) during the dieting period. In one study, disinhibition and hunger were significantly related to anxiety and depression while restraint was not (44). Another study concluded that elevated levels of anxiety persist in female patients throughout a VLCD course of treatment (45).
Also many patients complain about fatigue during a VLCD (4).
Conversely, our data suggest that hCG-treated volunteers rather improved their attitude towards their environment, in the sense of an enhanced well-being, less irritability and lack of fatigue. Since commercial preparations of hCG contains b-endorphin (39) and this neuropeptide has been demonstrated to affect the function of limbic-emotional circuits (21,58,5,28), we hypothesized that the b-endorphin fraction present in commercial preparations of hCG might account for the activity observed regarding mood control.
Additional studies remain to be performed to test the validity of this hypothesis.
1. Female obese volunteers participating in a double blind study, and submitted to the administration of an oral presentation of hCG plus a VLCD, decreased specific body circumferences and skinfold thickness from conspicuous body areas more efficiently than Placebo+VLCD -treated subjects.