EDITORIAL
Benefits of metformin in infertility of polycystic ovary
syndrome origin
Mohd Ashraf Ganie, Abdul Hamid Zargar
In the pathogenesis of polycystic ovary syndrome
(PCOS), insulin resistance has been considered as a
characteristic feature that is present in every case be it obese
or not. Considering that the obesity is present only in 50-60%
of PCOS women, insulin resistance should be regarded as an
important feature of this disease. Insulin is directly involved
in anovulation, testosterone production and lowering of
SHBG.
Metformin and thiazolidinedioes which are well
characterized insulin sensitizers were studied as possible
therapies of clinical manifestations of PCOS including
anovulation and infertility. Overall, the results of such studies
have been conducted to an optimistic view.
The first study reporting metformin action in PCOS
was published in Metabolism in 1994(1) but the first real
landmark was published in the N Engl J Med, in 1998(2) and
the results were indeed very promising (24% ovulatory rate
compared to 4% in placebo treated cases). Metformin added
to clomiphene was certainly even more impressive resulting
in 90% ovulatory rate (in comparison to 8% in the
clomiphene alone group). Many studies have been done
since then and almost all demonstrated increased ovulatory
rates with metformin use in PCOS. Besides, metformin
effect was proven to occur quickly, i.e., less than 2
months(3,4).
These studies prompted the first review done in 2003
by J. Lord et al(3). They concluded as well proven that
metformin had a great effectiveness in ovulation induction in
PCOS cases (46% vs 24% with placebo). The ovulation
attained with metformin and metformin plus clomiphene
citrate was 57%. Many of these studies, however, included
very few patients and were conducted for very short periods
of time(2,5). Increased pregnancy rates, on the contrary, were
much more difficult to demonstrate except in the cases that
were resistant to clomiphene.
Palomba et al reported the results of the first double
blind placebo controlled trial comparing metformin and
clomiphene citrate in non-obese PCOS patients, in relation
not only to ovulation increment but also and specially in
relation to pregnancy rates in PCOS women. Ovulation
induction didn’t appear to be different between the groups
but metformin was superior in terms of achieved pregnancies
(15.1% vs 7.2%), lower abortion rate and increased live
births(6). Few recent studies demonstrating the great
effectiveness of metformin in inducing ovulation concluded
that clomiphene citrate was as good if not better inducing
ovulation and also in terms of pregnancy rates and live birth
rates.
Neveu et al studied 154 women with PCOS. In spite of
the study period being short, ovulation was 75.4% in the
metformin alone group vs 50% in the clomiphene citrate
alone group. In the combination group it was 63,4%.
Pregnancy rates did not differ between the groups(7). A
meta-analysis done by Moll et al in 2007 analyzed the results
of 27 studies with the primary outcome being live birth rate.
There was no evidence for a significant difference in live birth
rates between metformin and clomiphene citrate or
metformin+clomiphene citrate vs clomiphene citrate alone.
In clomiphene citrate-resistant cases, on the contrary, the
addition of metformin increased live birth rate (RR=6.4). In
IVF the only recognized positive effect of metformin was to
reduce the number of hyperstimulation syndrome cases(8).
The PPCOS trial aimed to determine the optimal drug
regimen for initiation of ovulation induction in PCOS. This
study included 628 patients from 13 centers. Ovulation rate
was 29% in the metformin group, 49% in the clomiphene
citrate group and 60% in group with metformin
+clomiphene citrate. Life birth was 7%, 22% and 26%
respectively in those same groups(9).
The new study of Palomba et al with a duration of 6
months that demonstrated that ovulation was 55.4% with
metformin and 59.8% with clomiphene citrate while
1
IJEM 2007;11(3 & 2):1-2
pregnancies 10.8% with metformin vs 11.2% with
clomiphene citrate(10).
Patient differences are certainly the most plausible
explanation (going from genotype to the presence of obesity,
androgen levels, etc). But still there remain many
unexplained results. Both Legro’s and Palomba’s group
found that metformin had better results in women with
lower BMI. Being an insulin-sensitizing agent wouldn’t it be
much more logical that it worked better in obese women
where insulin resistance is much more marked? Palomba also
demonstrated that metformin’s positive effects leading to
pregnancy occur later than with clomiphene citrate’s
(median 7 months vs 5 months with clomiphene citrate), in
contrast to the induction of ovulation that Lord et al reported
to be precocious during metformin treatment [2 months](3).
Beyond these controversies and all the study design
errors another conclusion should be looked upon carefully:
In many of these studies ovulation rates are so high that it
raises a question if anovulation diagnosis has been correctly
done. Is it that progesterone levels of 4 ng/ml or higher
indeed indicate that an ovulation occurred? And if that is
correct is it not true that levels between 4 and for instance 8
ng/ml might indicate a worst quality ovulation or a worst
capacity to prepare the endomethrium to nidification, either
way resulting in less capacity to become pregnant?
Another important aspect concerns the diagnosis of
PCOS itself. For the diagnosis of anovulation how many
cycles should be studied to have a certain diagnosis of
anovulation? Many authors don’t even confirm anovulation
with at least one progesterone level in the lutheal phase of the
cycle. This may indicate that the women that are being
studied by different groups are indeed different from each
other, thus explaining the so different results.
Diagnosing PCOS according to the Rotterdam criteria
makes this problem even worst allowing the inclusion in
PCOS groups, of women that are not anovulatory. In our
opinion, ultrasound instead of being used for defining PCOS
could become a great help if used serially, as a tool to identify
developing follicles up to the point of ovulation and after.
2
We conclude that metformin has multiple benefits in
PCOS women especially in treating fertility. More studies
with higher doses may support the view
REFERENCES
1. Velasquez E, Mendoza S, Hamer T, Sosa F, Glueck C. Metformin
therapy in polycystic ovary syndrome reduces hyperinsulinemia,
insulin resistance, hyperandrogenemia, and systolic blood pressure,
while facilitating normal menses and pregnancy. Metabolism. 1994;
43: 647-654.
2. Nestler J, Jakubowicz D, Evans W, Pasquali R. Effects of metformin
on spontaneous and clomiphene-induced ovulation in the polycystic
ovary syndrome. N Engl J Med. 1998; 338 (26): 1876-1880.
3. Lord J, Flight I, Norman R. Insulin sensitizing drugs (metformin,
troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for
polycystic ovary syndrome. Cochrane Database Syst 2003; 3:
CD003053.
4. Lord J, Flight I, Norman R. Metformin in polycystic ovary
syndrome: systematic review and meta-analysis. BMJ 2003;327:951-
953.
5. Ganie MA, Khurana ML, Eunice M, Gulati M, Dwivedi SN, Ammini
AC. Comparision of efficacy of spironolactone with metformin in the
management of polycystic ovary syndrome: An open label study. J
Clin Endocrinol Metab 2004;89:2756-2762.
6. Palomba S, Orio F Jr, Falbo A, Manguso F, Russo T, Cascella T, et al.
Prospective paralell randomized double blind, double-dummy
controlled clinical trial comparing clomiphene citrate and metformin
as the first line treatment for ovulation induction in non-obese
anovulatory women with polycystic ovary syndrome. J Clin
Endocrinol Metab. 2005; 90: 4068-4074.
7. Neveu N, Granger L, St-Michel P, Lavoie HB. Comparison of
clomiphene citrate, metformin, or the combination of both for first-
line ovulation induction and achievement of pregnancy in 154
women with polycystic ovary syndrome. Fertil Steril. 2007;87(1):
113-20.
8. Moll E, van der Veen F, van Wely M. The role of metformin in
polycystic ovary syndrome: a systematic review. Hum Reprod
Update 2007;13(6): 527-37.
9. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP,
Carson SA, et al. Cooperative Multicenter Reproductive Medicine
Network. Clomiphene, metformin, or both for infertility in the
polycystic ovary syndrome. N Engl J Med. 2007; 356: 551-566.
10. Palomba S, Orio F Jr, Falbo A, Russo T, Tolino A, Zullo F.
Clomiphene citrate versus metformin as first-line approach for the
treatment of anovulation in infertile patients with polycystic ovary
syndrome. J Clin Endocrinol Metab. 2007; 92(9): 3498-3503.
ORIGINAL ARTICLE

Prevalence and etiology of male hypogonadism

M Eunice, M.L. Khurana, N Gupta, K. Kucheria**, A.C. Ammini
Departments of Endocrinology and Metabolism and Anatomy**, All India Institute of Medical Sciences, New Delhi

ABSTRACT

Introduction: Hypogonadism manifests clinically as defects of sexual differentiation, sexual development or infertility.
Material & Methods: We screened a total of 8,844 patients attending our endocrine clinic between June 2000 - May 2001 to
assess the frequency and etiology of male hypogonadism.
Objectives: To evaluate the frequency of male hypogonadism among patients attending the endocrine clinic and to assess the
clinical, hormonal and genetic profile of men with hypogonadism.
Material & Methods: Patients referred to the endocrine clinic of AIIMS hospital between the period of 1st June 2000 to 31st
May 2001 were screened for male hypogonadism. All patients underwent detailed history, physical examination, hormonal
analysis and genetic studies.
Results: The prevalence of male hypogonadism was found to be 1.2%. Out of these 6(5.45%) patients had ambiguous
genitalia. Among the 6 patients with ambiguous genitalia 4 had 46, XY karyotype and 2(siblings) had 46, XY/47, XXY mosaic
karyotype. Three cases had dysgenetic male pseudo hermaphroditism and one had 5 a reductase deficiency. Twenty eight
(25.45%) had gynaecomastia, 15(13.63%) had hypergonadotrophic hypogonadism, 36(32.72%) had hypogondotrophic
hypogonadism, 11(10%) had azoospermia and 16 (14.54 %) had delayed puberty.
Conclusion: We conclude that the male hypogonadism constituted 1.2% of referrals to our clinic. Age at presentation was quite
variable. Some cases were more than 40 years at the time of diagnosis which could be because of lack of awareness /
inadequate medical facilities. [IJEM 2007;(3&4):3-5]
Key words: Male hypogonadism, male pseudo hermaphroditism, ambiguous genitalia, mosaic Klinefelter syndrome,
gynaecomastia.

INTRODUCTION encoded by single genes(1). The enzyme of 3b-

Hypogonadism is a complex disorder manifesting as
disorder of sex differentiation or development and or
infertility. This condition is expressed in two ways depending
on which portion of the hypothalamopituitary gonadal axis is
affected. In hypogonadotropic hypogonadism, the
gonadotrops are low, implying an abnormality at the level of
hypothalamus or pituitary or both, while in hypergonado-
tropic hypogonadism, luteinizing hormone (LH) and follicle
stimulating hormone (FSH) are elevated, indicating a lack of
negative feedback by androgens produced by testes.
The pathway from cholesterol to androstenedione is
the same in the testis and adrenal and uses the same enzymes
Address for conrespodence:
Dr. A.C. Ammini, Professor and Head, Department of Endocrinology
and Metabolism, All India Institute of Medical Sciences, New Delhi-
110029, India.
Tele (O) : 91-11-6593645; Fax –91-11-26589162
E-mail: ammini @ medinst.ernet.in / aca433@yahoo.com
hydroxysteroid dehydrogenase (3bHSD) converts
pregnenolone to progesterone, 17-hydroxypregnenolone
(17OH-pregnenolone) to 17-hydroxyprogesterone (17OH-
progesterone), dehydroepiandrosterone (DHEA) to
androstenedione, and androstenediol to testosterone.
Defects in 3bHSD would lead to an increase in
pregnenolone, 17OH-pregnenolone, DHEA, and
androstenediol. P450c17 is also necessary in the proximal
stages of testosterone synthesis. P450c17 catalyzes the 17a-
hydroxylation of pregnenolone to 17OH-pregnenolone and
progesterone to 17OH-progesterone. The 17, 20 lyase
activity of P450c17 coverts 17OH-pregnenolone to DHEA,
but very little 17OH-progesterone is converted to
androstenedione, so that 17OH-progesterone is not a
precursor of human androgen synthesis(2,3). Defects in
either 17-hydroxylation or 17, 20 lyase activity of P450c17
will lead to an increase in respective steroid hormone
precursors. The conversion of androstenedione to

3
IJEM 2007;11(3&4):3-5
testosterone in the testis is catalyzed by type 3 17bHSD
(17bHSDIII), but this reaction can also be catalyzed by
17bHSD type V, which is widely expressed in extraglandular
tissue(4,5). In the present study, an attempt has been made to
evaluate the frequency of male hypogonadism among
patients attending the endocrine clinic and to assess the
clinical, hormonal and genetic profile of men with
hypogonadism.
MATERIAL AND METHODS
Patients referred to the endocrine clinic of AIIMS
hospital between the period of 1st June 2000 to 31st May 2001
were screened for male hypogonadism. All patients
underwent detailed history and physical examination. Those
with disorders of sexual differentiation (46, XY karyotype,)
lack of secondary sexual development or infertility (with
azoospermia) were included for further evaluation.
Genetic analysis
Conventional cytogenetic analysis was done on
peripheral blood using standard techniques. Karyotyping was
done on G-banded metaphases obtained from 72-hour
cultures.
Hormonal analysis
Testosterone was estimated by radioimmunoassay
method with IMMUNOTECH Radioimmunoassay kit
(France). Human Luteinizing Hormone (hLH), Human
Follicle-stimulating hormone (hFSH), and Human
Prolactin (hPRL) levels were estimated by Immuno-
radiometric method from MEDICORP kits (Canada). DHT
was estimated in these samples by radioimmunoassay
method after celite chromatography.
HCG stimulation test
hCG stimulation test was done for children with
ambiguous genitalia or undescended testes who had LH,
FSH levels in the normal range. 2000 IU (500 IU for children
less than 5 years) of hCG intra-muscularly was given for 3
days and the blood sample was collected on the 4th day for
testosterone estimation. Same sample was used for DHT also
as and when required.
GnRH stimulation test
GnRH stimulation was done for children with
ambiguous genitalia. 100µg of Gonadotrophin releasing
hormone (GnRH) was injected intravenously and samples
were collected for LH & FSH -15, 0, 30, 60, 120 minutes.
Samples were stored at -20oC till assayed.
RESULTS
8,844 new patients were registered in the Endocrine
clinic during a one year period (from 1st June 2000 to 31st
May 2001). Male hypogonadism accounted for 110 referrals.
Age of patients ranged from 4 months to over 40 years. There
were 6 children with ambiguous genitalia (age 4 months to 14
years), 93 complained of disorders of pubertal development
4
11 had infertility due to azoospermia. Among them with
disorders of pubertal development, 15 were hypogonado
trophic hypogonadism, 36 were hypergonadotrophic
hypogonadism, 11 had idiopathic gynecomastia and 14 had
constitutional delay in growth and development. Dysgenetic
male pseudo hermaphroditism was diagnosed in 3 of the 6
cases with ambiguous genitalia. Two had 46, XY/47, XXY
karyotype and these were siblings. The degree of deficit
correlated with the percentage of abnormal (47, XXY) cell
lines. While the elder sibling with 30% 47, XXY cell lines had
the urethral opening over the distal 3rd of the phallus, the
younger sibling with 70% abnormal cell lines had perineal
urethral opening. The testosterone response to hCG was also
greater in the older sibling.
One patient was diagnosed to have 5a reductase 2
deficiency. His history was remarkable as he was reared as a
girl till puberty, when male secondary sexual development
was noticed; this patient opted for a male gender. His LH,
FSH, testosterone levels were within normal male range, but
T/DHT ratio was 37 and raised to 85 following hCG
stimulation.
DISCUSSION
Patients with hypogonadism exhibit a wide spectrum of
phenotypes, ranging from disorders of sexual differentiation
to infertile or impotence. Prevalence of hypogonadism was
found to be 38.7% in men of 45 years or above who visited
primary care practices in the United States(6). In a five years
(1999–2004) clinical and inheritance study of Kallmann
syndrome from twelve Jordanian and Palestinian families
(age 4 - 46 years) were evaluated. Among 26 males, nine boys
aged 4 - 14 years presented with cryptorchidism and
microphallus, all other males presented with delayed puberty,
hypogonadism and/or infertility(7).
In an epidemiological study, the incidence of
ambiguous genitalia in neonates from Germany, 80 cases
were identified within a 2-year study period(8). They
reported an incidence of 2 per 10,000 births with ambiguous
genitalia per year in Germany. Prevalence was higher in
infants from non-German family background. In more than
50% of infants a definite diagnosis was lacking even at the age
of 6 months.
A retrospective gender assessment study of 250 patients
in Seattle, WA, from January 1981 through December 2005
evaluated the frequency of disorders of sex development.
They observed, 177 were infants, 46 were children or
adolescents, and 27 had a multisystem genetic condition. The
most common disorders were congenital adrenal hyperplasia
(14%), androgen insensitivity syndrome (10%), mixed
gonadal dysgenesis (8%), clitoral/labial anomalies (7%),
hypogonadotropic hypogonadism (6%), and 46, XY small-
for-gestational-age males with hypospadias (6%)
respectively(9).
Though there is a paucity of data on the prevalence and
Prevalence and etiology of male hypogonadism
etiology of male hypogonadism from India, six cases of true
hermaphroditism were reported from North India in one
and a half decades period(10). The authors reported that the
age at presentation varied from 2 months to 41 years and
symptoms ranging from ambiguous genitalia to a lower
abdominal mass. All patients had perineoscrotal hypospadias
with varying degrees of labioscrotal fusion. Age at
presentation for the present study ranged from 2 months to
40 years for the 110 males with hypogonadism. Among them,
33 % were cases of hypogonadotrophic hypogonadism while
28% had isolated (idiopathic) gynaecomastia with normal
gonadal functions. Six patients had ambiguous genitalia.
Among them was a pair Siblings with 46, XY / 47, XXY
karyotype and genital ambiguity, a rarer occurrence (11). One
patient with DSD and virilized at puberty and changed to
male gender(12).
CONCLUSION
We conclude that the male hypogonadism constituted
1.2% of referrals to our clinic. Age at presentation was quite
variable. Some cases were more than 40 years at the time of
diagnosis which could be because of lack of awareness /
inadequate medical facilities.
Acknowledgement
This study was funded by Indian Council of Medical
Research, grant no. 5/10/57/95-RHN. We would like to thank Ms.
Kamal Kishori for technical assistance.
Eunice M et al
REFERENCES
1. Miller WL Molecular biology of steroid hormone synthesis. Endocr
Rev 1988;9: 295–318.
2. Auchus RJ, Lee TC, Miller WL. Cytochrome b5 augments the 17,20
lyase activity of human P450c17 without direct electron transfer. J
Biol Chem 1998;273: 3158–3165.
3. Flück CE, Miller WL, Auchus RJ. The 17,20 lyase activity of
5
cytochrome P450c17 from human fetal testis favours the D
steroidogenic pathway. J Clin Endocrinol Metab 1999;88: 3762–3766.
4. Peltoketo H, Luu-The V, Simard J Adamski J. 17b-hydroxysteroid
dehydrogenase (HSD)/17-ketosteroid reductase (KSR) family;
nomenclature and main characteristics of the 17-HSD/KSR
enzymes. J Mol Endocrinol 1999;23: 1-11.
5. Dufort I, Rheault P, Huang SR, Soucy P, Luu. The V Characteristics
of a highly labile human type 5 17bhydroxysteroid dehydrogenase.
Endocrinology 1999;140: 568–574.
6. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C.
Prevalence of hypogonadism in males aged at least 45 years: the HIM
study. Int J Clin Pract 2006;60(7): 762-9.
7. Mousa A AbuJbara, Hanan A Hamamy, Nadim S Jarrah, Nadima S
Shegem, Kamel M Ajlouni. Clinical and inheritance profiles of
Kallmann syndrome in Jordan. Reprod Health 2004;1: 5.
8. Thyen U, Lanz K, Holterhus PM, Hiort O. Epidemiology and initial
management of ambiguous genitalia at birth in Germany. Horm Res
2006;66(4): 195-203.
9. Parisi MA, Ramsdell LA, Burns MW et al. A Gender Assessment
Team: experience with 250 patients over a period of 25 years. Genet
Med 2007;9(6): 348-57.
10. Bansali A, Mahadevan S, Singh R, Rao KL, Garewal G. True
hermaphroditism: clinical profile and management of six patients
from North India. J Obstet Gynaecol 2006;26(4): 348-50.
11. Eunice M, MP Baruah, ML Khurana, AC Ammini. Two Siblings with
Ambiguous Genitalia and 46 XY / 47XXY Karyotype, Pediatric
Research 2001;49(6) Part 2: 56A.
12. Marumudi Eunice, Pascal Philibert, Bindu Kulshreshtha et al.
Molecular diagnosis of 5 a-reductase-2 gene mutations in two Indian
families with male pseudohermaphroditism 2007. “In press” Asian
Journal of Andrology.
5
ORIGINAL ARTICLE

Ketonuria and Ketonemia in type 2 Diabetes mellitus patients

attending an Indian endocrine clinic

Sanjay Kalra, Bharti Kalra, Amit Sharma

Bharti Hospital, Karnal, Haryana, India

ABSTRACT

Introduction: The occurrence of ketonuria in type 2 diabetes been reported by various authors studying separate ethnic groups.
There has been an explosion of type 2 diabetes in the Indian subcontinent, and this has been accompanied by an increase in
the research done in this field. However, not much emphasis has been laid on finding the incidence of ketosis- prone type 2
diabetes in the South Asian population.
Objectives: This study aims to assess the frequency of ketonuria and ketonemia amongst type 2 diabetic patients attending an
endocrine OPD in northern India.
Material and Methods: Two hundred patients of type 2 diabetes mellitus, at risk of developing ketosis, were tested for urine
ketones. Any person with diabetes, mellitus not known to be a case of type 1 diabetes mellitus, with any of these inclusion
criteria: fasting blood glucose >200 mg%, post prandial or casual blood glucose >300 mg%, abdominal symptoms, any acute
illness including altered sensorium, an ‘atypical’ presentation, pregnancy and alcohol intake, was included in the study.
Results: The most frequent indications for ketone testing were post prandial or casual blood glucose >300 mg%, fasting blood
glucose >200 mg% and first presentation to the hospital. The highest yields, of ketonuria were in patients of high blood
glucose and acute illness if seen in absolute terms, or as a percentage of total ketonuric patients. Three patients had positive
ketonemia, including one with acute pancreatitis. Percentage – wise, ketonuria was more often seen in patients with
abdominal symptoms, pregnancy, alcohol intake and acute illness like balano – posthitis, gastroenteritis and tuberculosis.
Moderate or high ketonuria was observed more often in pregnancy and abdominal symptoms. Ketonuria was frequently
encountered (17%) in “type 2” diabetic individuals with specific signs, symptoms or presentations. Ketonuria is frequent,
while ketonemia is infrequent (but not absent) in type 2 diabetic patients in India.
Conclusion: The study reveals that urine ketone testing should be done in so called type 2 diabetes patients with specified
symptoms or presentations. This economical investigation plays an important role in deciding the appropriate treatment for
the patient, and prevents potentially fatal delays in instituting insulin therapy. [IJEM 2007;(3&4):7-9]
Key words: Ketonuria, Ketonemia, type 2 diabetes mellitus

INTRODUCTION was named Type 1.5 diabetes or ‘Flatbush’ diabetes(4).

Diabetes mellitus was earlier classified as IDDM
(insulin dependent diabetes mellitus) and NIDDM (non
insulin dependent diabetes mellitus). The latter entity was
thought to be non insulin requiring and ketoacidosis was
thought to be a complication limited to IDDM.
Gradually, with advances in understanding the patho
physiology of the disease, many variants of the illness were
noted. Type 2 diabetes mellitus (earlier named NIDDM) was
seen to present with ketonuria, and later get controlled with
oral hypoglycemics, in American-Africans(1,2,3). This entity
Address for Correspondance:
Dr. Sanjay Kalra, Endocrinologist
Bharti Hospital, Karnal, Haryana, India
E-mail: bhartikalra@yahoo.co.in
The occurrence of ketonuria in type 2 diabetes been
reported by various authors studying separate ethnic
groups(5,6,7). This entity is thought to be less common
amongst Asians than Africans.
There has been an explosion of type 2 diabetes in the
Indian subcontinent, and this has been accompanied by an
increase in the research done in this field. However, not
much emphasis has been laid on finding the incidence of
ketosis- prone type 2 diabetes in the South Asian population.
This study aims to assess the frequency of ketonuria
and ketonemia amongst type 2 diabetic patients attending an
endocrine OPD in northern India. It also aims to assess the
cost-effectiveness of advising blood and urinary ketone
estimation in different subgroups of patients with diabetes
mellitus.

7
IJEM 2007;11(3 & 4):7-9

MATERIAL & METHODS diagnosed diabetes than patients without ketonuria. There
Two hundred patients of type 2 diabetes mellitus was no significant difference with regard to gender
fulfilling the inclusion criteria, presenting to our endocrine distribution and body mass index (BMI). The symptoms,
OPD located in northern India were tested for urine ketones signs or presentations which the patients had are detailed in
by dipstick method (Keto – Diastix from Bayer Diagnostics). Table 2.
Some patients were also assessed for ketonemia using Table 2: Indications and results of urine ketone testing
Optium blood ketone sticks (Abbott England). Blood ketone Indication All patients Ketonuria Ketonuria
testing was not possible in many patients because of negative positive
(n=200) (n=166) (n=34)
intermittent availability of sticks during the study period, and
because of paucity of funds in the resource – challenged Fasting blood glucose
>200 mg% 69 (34.5%) 54(32.53%) 15(44.11%)
centre.
Post prandial or casual
The inclusion criteria were all of the following: blood glucose
1) Any person with diabetes mellitus not known to be a >300 mg% 92(46.0%) 77(46.38%) 15(44.11%)
case of type 1 diabetes mellitus. Abdominal symptoms:
2) Any person with diabetes mellitus not on chronic nausea, vomiting,
abdominal pain. 11(5.5%) 6(3.61%) 5(14.70%) *
insulin therapy for more than 3 months.
Any acute illness
3) Any person presenting with one or more of the
including altered
following symptoms, signs or presentations: sensorium 30(15%) 21(12.6%) 9(26.47%) *
a) fasting blood glucose >200 mg%, b) post prandial or First presentation to
casual blood glucose >300 mg%, c) abdominal the hospital 58(29%) 56(33.73%) 2(5.8%)
symptoms: nausea, vomiting, abdominal pain, d) any An ‘atypical’ presentation,
acute illness including altered sensorium, e) first as assessed by
presentation to the hospital, f) an ‘atypical’ multipurpose diabetes
worker 17(8.5%) 14(8.43%) 3(8.82%)
presentation, as assessed by the multipurpose diabetes
Pregnancy 4(2%) 1(0.6%) 3(8.82%) *
worker, g) pregnancy and h) alcohol intake in the
preceding 24 hours. Alcohol intake in the
preceding 24 hours. 4(2%) 2(1.2%) 2(5.8%) *
Each patient fulfilling inclusion criterion 1, 2 and 3 was
* = p < 0.05
tested for urinary ketones by dipstick (Keto Diastix from
Bayer Diagnostics, Germany). The 48 patients had a blood The most frequent indications for ketone testing were
ketone estimation done (Optium Ketone sticks from Abbott post prandial or casual blood glucose >300 mg%, fasting
Laboratories, England). blood glucose >200 mg% and first presentation to the
Results were analyzed to assess the correlation of hospital. The highest yields, of ketonuria were high blood
different variables with ketonuria and ketonemia. glucose and acute illness if seen in absolute terms, or as a
percentage of total ketonuric patients.
The same figures, when calculated as percentage total
RESULTS
subjects for a particular indication, are shown in Table 3. The
All 200 patients were included in the study, 48 of whom
highest percentage of positivity was seen in pregnancy,
had a blood ketone determination done.
alcohol intake, abdominal symptoms and acute illness.
The characteristics of ketonuria positive and ketonuria Moderate or high ketonuria was observed most often in
negative patients are presented in Table 1. pregnancy and abdominal symptoms. The lowest yield of
Table 1: Patient characteristics in both groups ketonuria was in patients with post prandial or casual blood
Ketonuria Ketonuria glucose >300 mg% and first presentation to the hospital.
positive negative
The 48 patients who had blood ketone tested are
(n=34) (n=166)
detailed in Table 4. The patients with positive ketonemia
Age (mean ± S.D) yrs 36.21 ± 6.04 41.23± 5.32 included a total of three patients. All had abdominal
Gender (M/F) 20/14 97/69 symptoms and two of them had high fasting blood glucose
BMI (mean ± S.D) kg/m 2
27.28 ± 2.23 26.26 ± 2.12 values in the setting of acute illness. One of the ketonemia
Duration of diabetes positive patients (5.6 mmol/l) was a 24 year old male with
(mean ± S.D) yrs 3.42 ± 1.92 6.51 ± 2.91 abdominal symptoms, who was later diagnosed as having
H/o prior insulin use (%) 3/34(8.82%) 27/166(16.26%) acute pancreatitis. The other two were lean women aged 50 -
60 years old with gastroenteritis, dehydration and altered
Newly diagnosed
diabetes (%) 9/34(26.47%) 22/166(13.25%)
sensorium. Both responded to intravenous fluids and
insulin.
Ketonuria positive patients were younger, had diabetes
of shorter duration, and were more likely to have newly The details of the ketonuria – positive ‘acute illness’

8
Ketonuria and Ketonemia in type 2 diabetes mellisus..................... Sanjay Kalra et al

which were an indication for testing ketones are: The maximum number of ketonuric patients had
gastroenteritis (2/9), tuberculosis (2/9) and balanoposthitis fasting blood glucose >200 mg% or postparandial blood
(5/9). The ‘atypical’ presentations with ketonuria which glucose >300 mg%. Percentage – wise, ketonuria was more
prompted a multipurpose diabetes worker to ask for ketone often seen in patients with abdominal symptoms, pregnancy,
test were profuse sweating (1/3), and obese adolescent (2/3). alcohol intake and acute illness like balano–posthitis,
gastroenteritis and tuberculosis. Abdominal symptoms,
Table 3: Ketonuria positivity in different indications acute illness and pregnancy were associated with higher
incidence of moderate or large ketouria.
Indication Total No (%) Ketones Ketones
of ketone trace/ moderate/ These findings have major diagnostic and therapeutic
positivity small no. large implications. Urine ketone testing should be done in so
Fasting blood called type 2 diabetes patients with specified symptoms or
glucose >200 mg% 69 15(21.73%) 10(14.49%) 5(7.2%) presentations. It is a simple and cost effective investigation
Post prandial or which has bearing on further management of the patient.
casual blood glucose Physicians, nurses, laboratory technologists and other
>300 mg% 92 15(16.30%) 10(10.86%) 5(5.43%)
diabetes care provides should be sensitized to the existence of
Abdominal symptoms: this subset of patients with diabetes. They usually respond to
nausea, vomiting,
abdominal pain 11 5(45.45%) 1(9.09%) 4(36.36%)
short term insulin therapy and remain well controlled on
diet, exercise and oral drugs once the acute illness is resolved.
Any acute illness
including altered
The difficulty in classifying these patients should not mean
sensorium 30 9(30%) 3(10%) 6(20%) that they shouldn’t be treated appropriately(8).
First presentation The diagnosis may be missed, and proper therapy
to the hospital 38 2(5.26%) 1(2.63%) 1(2.63%) delayed, if urinary ketone estimation is not performed, multi
An ‘atypical’ purpose diabetes workers can be trained to recognize
presentation, as ‘atypical’ presentation, and order urinary ketones for a pre
assessed by selected list of indications in certain ethnic groups. This will
multipurpose help in early institution of appropriate therapy.
diabetes worker 17 3(17.64%) 1(5.88%) 2(11.76%)
The study suffers from some limitations. Blood
Pregnancy 4 3(75%) 1(25%) 2(50%)
Alcohol intake in the
ketones were not estimated in all subjects, due to paucity of
preceding 24 hours 4 2(50%) 0 1(25%) resources. A bias is evident towards ordering blood ketones in
‘more sick’ patients. The under priveliged character of the
Table 4: Ketonemia positivity in different indications
Indication All patients Ketonemia Ketonemia Ketonemia
(n=48) positive equivocal negative
( >5.6 mmol/l) (2.6-5.6 mmol/l) (<2.6 mmol/l)
(n=3) (n=0) (n=45)
Fasting blood glucose >200 mg% 19(39.58%) 2(66.66%) 0 17
Post prandial or casual blood glucose >300 mg% 23(47.91%) 0 0 23
Abdominal symptoms: nausea, vomiting,abdominal pain. 7(14.58%) 3(100%) 0 4
Any acute illness including altered sensorium. 7(14.58%) 2(66.66%) 0 5
First presentation to the hospital 0 0 0 0
An ‘atypical’ presentation ,as assessed by multipurpose diabetes worker 3(6.25%) 0 0 3
Pregnancy 0 0 0 0
Alcohol intake in the preceding 24 hours. 2(4.16%) 0 0 2

DISCUSSION
In this study ketonuria was frequently encountered
(17%) in “type 2” diabetic individuals with specific signs,
symptoms or presentations. Ketonemia, however, was much
less frequently seen(1.5%). Similar observations regarding
ketonuria have been made by researchers from various parts
of the world(4, 5, 6). Not much work, however, has been
done regarding ketonemia in “type 2” diabetes. This study
has shown that the ketonuria is frequent, while ketonemia is
infrequent (but not absent) in type 2 diabetic patients in
India.
area where this study was performed has meant that islet cell
antibodies, GAD antibodies or other auto immune markers,
and glycated haemoglobin could not be estimated in the
subject population.
In spite of these limitations, however, this work will
help in redefining investigative and therapeutic strategies in
Indian type 2 diabetes patients with acute illness and
hyperglycemia.
CONCLUSION
The study reveals that urine ketone testing should be

9
done in so called type 2 diabetes patients with specified
symptoms or presentations. This economical investigation
plays an important role in deciding the appropriate treatment
for the patient, and prevents potentially fatal delays in
instituting insulin therapy.
REFERENCES
1. Umbierrez GE, Casals MMC, Gebhart SSP et al. Diabetic
ketoacidosis in obese African -Americans. Diabetes 1995;44: 79-85.
2. Banerji MA, Chaiken Rl, Huey H et al. GAD antibody negative in
NIDDM in adult back Subjects with diabetic ketoacidosis and
increased frequency of human leukocyte antigen DR3 and DR4.
Diabetes 1994; 43: 741-5.
2a. Winter WE, Maclaren NK, Riley WJ et al. Maturity – onset diabetes of
youth in black Americans. N Engl J Med 1987;316: 285- 91.
3. Banerji MA, Lebovitz HE. Remission in non- insulin – dependent
diabetes mellitus: clinical Characteristics of remission and relapse in
black patients. Medicine (Baltimore) 1990; 22: 345-54.
4. Umpierrez GE, Casals MM, Gebhart SP et al. Diabetic ketoacidosis
in obese African – Americans. Diabetes 1995;44: 790-5.
5. Ahren B, Corrigan CB. Intermittent need for insulin in a sub group of
diabetic patients in Tanzania. Diabet Med 1985; 2:262-4.
6. Banerji MA, Chaiken Rl, Huey H et al. GAD antibody negative
NIDDM in adult black subjects with diabetic ketoacidosis and
increased frequency of human leukocyte antigen DR3 and DR4.
Flatbush diabetes. Diabetes 1994;43: 741-5.
7. Yamada K, Nonaka K. Diabetic ketoacidosis in young obese Japanese
men. Diabetes Care 1996;19: 671.
8. Perret JL. Bifane E, Nigou – Milama et al. Types of sugar diabetes
encountered in internal medicine in Gabon. Med Top 1996;56: 55-8.
ORIGINAL ARTICLE

The prognostic significance of thyroid antibodies in patients

with hyperthyroidism treated with Carbimazole
Sandip Kumar Batabyal, Sundip Chatterjee
B.R. Singh Hospital, Eastern Railway, Kolkata and Park Medical Research Society, Kolkata

ABSTRACT

Introduction: Measurement of antithyroglobulin (TgAb) and antithyroperoxidase (TPOAb) antibodies have been performed
widely for the clinical diagnosis of autoimmune thyroid diseases. The presence of antibody markers will provide the
physicians an idea of the long term prognosis and the patients can be counselled accordingly.
Objectives: The aim of the present study was to monitor the clinical significance of serum TgAb and TPOAb during and after
treatment with Carbimazole in hyperthyroidism.
Materials and Methods: Seventy six patients were treated for two years and then followed for an additional one and a half year.
The patients were classified into the following groups: group I, patients negative for both TgAb and TPOAb before and
during the two years of treatment, group II, patients positive for TPOAb but negative for TgAb before and during the two
years of treatment and group III, patients who were positive for both TgAb and TPOAb before and during therapy. The
antibody markers were estimated by immunoradiometric and radioimmunoassay methods.
Results: The relapse rates after discontinuation of treatment in these groups were 45% (9 of 20), 32% (10 of 31) and 17% (4 of
23) respectively; the value in group I was significantly higher than that in group III (p<0.01). The results suggest that the
presence of TPOAb and TgAb may influence the prognosis of hyperthyroid patients treated with carbimazole.
Conclusion: We conclude that the relapse rate in drug-treated patients who had positive antithyroid antibody titres (TgAb and
TPOAb ) was lower than that in patients in whom both tests were negative. [IJEM 2007;(3&4):11-13]
Key Words: Thyroid antibodies (TgAb and TPOAb), hyperthyroidism, carbimazole, autoimmune thyroid disease

INTRODUCTION sensitive radioimmunoassay for serum TPOAb has been

Autoimmune thyroid disease (AITD) is characterised
by the presence of circulating autoantibodies directed to
thyroid antigen. The majority can be diagnosed by clinical
presentation and their antibody profiles to thyroglobulin
(TgAb) and thyroid microsomes (TPOAb). Thyroid
microsomal antibodies have been recently proven to be
directed to thyroid peroxidase (TPO) and at least some TPO
antibodies inhibit the formation of thyroid hormones(1). In a
survey of disease free population conducted by the National
Health and Nutrition Examination III, USA it was found that
a large proportion of US population unknowingly have
laboratory evidence of thyroid disease which supports the
usefulness of screening of T4, TSH and thyroid antibodies
for early detection(2). Diagnostic evaluation of AITD by a
Address for correspondence:
Consultant Medical Biochemist Nightingale Diagnostic & Medicare Pvt.
Ltd. 11, Shakespeare Sarani, Kolkata 700071
reported by us(3). In our earlier observation we had
demonstrated that among the normal population in Eastern
India, TgAb was positive in 7.7% and TPOAb in 9.2% and the
positivity were more prevalent in women than men with
increasing age group(4). About 20% of patients with
hyperthyroidism due to Graves’ disease developed
hypothyroidism subsequent to discontinuation of
antithyroid drug therapy(5,6). In such patients the thyroid
destruction was thought to be due to autoimmune
mechanisms and/or the presence of TSH-blocking
antibodies(5). Controversy exists regarding the relapse rate
in-patients with Graves’ disease who had high serum TgAb
and TPOAb titres(7,8). To investigate further the clinical
significance of thyroid antibodies in hyperthyroidism, we
determined the results of antithyroid drug therapy in
hyperthyroid patients subdivided according to their TgAb
and TPOAb status and during therapy.

11
IJEM 2007;11(3 & 4):11-13

MATERIALS AND METHODS TgAb and TPO-Ab negative were classified into group I (21
A total of 91 participants (15 normal and 76 patients) patients). Group II (31 patients) consisted of those patients
were recruited for this study. Normal sera were obtained who were initially and continued to be TgAb negative and
from 15 healthy subjects-10 female and 5 male, aged between TPO-Ab positive during two year of treatment. Group III (24
19 and 56 yrs). Pathological sera were obtained from 76 patients) consisted of those patients who were initially and
patients with previously untreated hyperthyroidism visiting continued to have positive titres for both TgAb and TPO-Ab.
the thyroid and medical clinics. There were 14 men and 62 One patient who was positive for both the antibodies initially
women aged between 20 and 54 yrs. Hyperthyroidism was became negative for TgAb during therapy and one patient
diagnosed on the basis of medical history, clinical findings, who was negative for both the antibodies initially became
serum thyroid hormone levels and thyroidal 131I uptake study. positive for TPO-Ab only during therapy. Since these two
Goiter size was estimated by palpation followed by both patients did not fit into the above three groups they were
initial and periodical neck girth assessment during follow-up. eliminated from the study. Comparisons were made among
In the present series, 58 hyperthyroid patients had definite the groups with respect to thyroid function at the time of
ophthalmopathy and thus could be classified as Graves’ initial medical examination, relapse rate, initial goiter size and
disease patients. The other 18 patients had diffuse goitres time from discontinuation of therapy to relapse. The relapse
with no nodules in them. However, the cause of rate between individual groups were compared statistically
hyperthyroidism could not be determined with certainty. and p<0.05 was considered significant.
Thyroid function tests
The 24 hr thyroidal 13lI uptake (normal range 20-45%) RESULTS
was measured by a standard method as approved by Radiation The patients’ initial thyroid antibody levels according
Medicine Centre, Bhaba Atomic Research Centre, Mumbai. to the classification of different groups are shown in Table l.
Serum T3, T4 and TSH concentrations were estimated in Serum thyroid hormone levels in three groups at the time of
duplicate using RIA kits obtained from Bhaba Atomic their initial evaluation are shown in Table 2. The results did
Research Centre, Mumbai. Serum free T4 (FT4) level was not differ significantly among the groups. Table 3 shows the
measured by a RIA kit obtained from Institute of Isotopes Co. mean relapse rate, initial goiter size, times between
Ltd, Budapest. The normal ranges were 0.7 to 2.0 ng/ml, 5.5 discontinuation of treatment and diagnosis of relapse after at
to 13.5 mg/dl, 0.25 to 5.0 to 13.5mg/ml and 12 to 23 pmol/l least one and a half year of discontinuation of treatment in the
respectively. three groups. The mean goiter size and the time period
Measurement of antithyroid antibodies
Table 1: Initial serum thyroid autoantibody levels in different
Serum TgAb was determined by a ‘sandwich’ groups of hyperthyroid patients
immunoradiometric method and TPO-Ab by a RIA method
with protocol and kits obtained from M/S Immunotech, a Groups TgAb TPOAb
Beckman Coulter Company, France. The assay sensitivities (U/ml) (U/ml)
for TgAb and TPO-Ab are 10.0 U/ml and 15.0 U/ml I (n=21) 72.6±11.3 39.4±5.2
respectively. The intraassay coefficient of variation were 5.8 II (n=31) 81.5±7.2 185.8±21.7
and 8.1 respectively using 10 serum replicates. The healthy III (n=24) 190.6±32.5 232.5±29.4
normal subjects exhibit, below 100.0 u/ml and 50.0 u/ml Normal (n=15) 41.3±14.5 23.7±10.5
Normal limit <100.0 <50.0
values for TgAb and TPO-Ab respectively.
Treatment protocol Figures in parenthesis indicate number of subjects
The patients were treated for a period of two years with Results are in mean±S.D.
carbimazole and were followed for at least one and a half year
after termination of treatment [18 to 38 months, mean Table 2: Initial thyroid function tests in patients with hyperthyroid
26.5±6.8 (SD) months]. The thyroid function tests were state
normal in all patients when treatment was discontinued. Serum Serum Serum
131
Serum I uptake
Relapse of hyperthyroidism was diagnosed on the basis of Group T3 T4 TSH FT4 24 hr
clinical history and physical finding, elevated serum thyroid (ng/ml) (mg/dl) (m/ml) (pmol/L) (%)
hormone concentrations and increased 24 hrs thyroidal I 131

I (n=21) 3.1±l.02 14.5±l.2 0.21±0.06 28.5±3.2 58.3±9.1

uptake. The initial doses of carbimazole were 30mg daily and II (n=31) 4.2±1.1 16.4±1.3 0.24±0.08 34.0±5.1 66.5±8.7
thyroid function was evaluated every month. The III (n=24) 3.7±l.4 15.6±1.5 0.19±0.1 30.7±4.4 62.8±7.6
carbimazole dose was gradually decreased as the serum Normal 1.3±0.28 8.5±1.1 1.7±0.45 16.4±2.2 32.0±4.2
thyroid hormone levels declined to normal but in no patient (n=15)
Normal [0.72- 2.0] [5.5-13.5] [0.25-5.0] [12-23] [20-45]
for whom data were included here was it discontinued before range
two years had elapsed. Serum TgAb and TPO-Ab titres were
also measured every month. During the two-year period of Figures in first bracket indicate number of subjects
treatment, the patients who were initially and continued to be Results are in mean±S.D

12
Prognostic significant of thyroid antibodies ...........................
Table 3: Relapse rate (RR), initial goiter size and time between
discontinuation of carbimazole and diagnosis of relapse
Group No.of No. of RR Initial goiter Time from
Cases Relapse (%) size (g) discontinuation
of therapy
to relapse
(Months)
I 20 9 45 33.5±9.0 15.4±3.6
(18-50)
II 31 10 32 40.6±1.0 12.8±4.5
(22-65)
III 23 4 17 42.3±10.0 14.5±3.7
(23-62)
Results are in mean±S.D
between discontinuation of therapy and relapse were almost
similar. However, the relapse rates among the three groups
differed significantly (p<0.05). Pairwise comparison
revealed that the relapse rate in group I was significantly
higher (p<0.01) than that in group III but the rates in group I
and II were not statistically significant. Among 54 patients
who were positive for TPO-Ab (group II and III), 14(25%)
relapsed. This relapse rate was significantly lower (p<0.05)
than that (45% ) in the group I with persistently negative
TPO-Ab titres. When the patients were classified on the basis
of the presence or absence of TgAb, 4 of 2.1 patients (17%) of
TgAb positive cases and 19 of 51 (37%) of the TgAb negative
patients had relapsed (p<0.02). Three patients (1 in group I
and 2 in group III) underwent subtotal thyroidectomy after
they had relapsed and then had received carbimazole therapy.
Lymphocytic infiltration and destruction of follicular
structures were noted in the thyroid tissues obtained in two
patients who had positive titres for both TgAb and TPO-Ab.
In one patient whom both the titres were negative, no thyroid
lymphocytic infiltration was seen and there was less
destruction of follicular structure.
DISCUSSION
The evolution from hyperthyroidism to
hypothyroidism probably results from thyroid destruction
induced by autoimmune mechanism (TgAb, TPO-Ab) and
/or TSH - blocking antibodies(5). Indeed, marked
lymphocytic infiltration and destruction of follicular
structures were found in this study in the thyroid tissues
obtained at the time of subtotal thyroidectomy of patients
who were TgAb and TPO-Ab positive. The higher incidence
of hypothyroidism after subtotal thyroidectomy in Graves’
disease with positive TPO-Ab had already been reported (9).
In our study a significantly lower rate of relapse of
hyperthyroidism occurred in those patients who were
positive for both TgAb and TPO-Ab, compared to those who
had negative titres for both antibodies. The likely mechanism
for the difference is that those patients with both positive
titres had some antibody-mediated destruction of thyroid
cells. Our findings are in agreement with earlier study(10)
but contradict with other studies(7,8). The significance of
TgAb remains controversial, some reports indicate that TgAb
Sandip Kumar et al
do not manifest antibody-dependant cell-mediated
cytotoxicity similar to that of antimicrosomal (TPO-Ab)
antibodies(10,11,12) whereas other reports maintain that Tg-
TgAb action can mediate cytolysis of thyroid cells(13,14).
Our result support the contention that decreased thyroid
function in patients with hyperthyroidism previously treated
with an antithyroid drug is probably due to the destruction of
thyroid tissue resulting from the presence of TgAb and Tro-
Ab. We conclude that the prognosis for long term remission
in carbimazole-treated hyperthyroid patients is better who
have elevated serum TgAb and TPO-Ab concentrations.
CONCLUSION
We conclude that the relapse rate in drug-treated
patients who had positive antithyroid antibody titres (TgAb
and TPOAb ) was lower than that in patients in whom both
tests were negative.
Acknowledgement
The authors thank Mr. K.B Rajkurnar, Physicist, B.R Singh Hospital,
Eastern Railway, Kolkata for his technical assistance.
REFERENCES
1. Mariotti S, Caturegli P, Piccolo P, et al. Antithyroid peroxidase
autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990;71:
661-69.
2. Serum TSH, T4 and thyroid antibodies in the United States population
(1988 to 1994): National Health and Nutrition Examination Survey
(NHANES III). J Clin Endocrinol Metab 2002;87(2): 489 -99.
3. Batabyal SK, Das AK. Antibodies to thyroid peroxidase in patients with
thyroid diseases Ind J Nucl Med 1996;11(2): 134-136.
4. Batabyal SK. Prevalence of autoantibodies in thyroid pathophysiology
among railway population. In: Saha N, Banerji AK, Das TK,
Chakraborty S, editors. Proceedings of the National Seminar on Recent
Advances in Molecular Physiology, University of Kalyani, W .B. 2002.
pp. 55-57.
5. Wood LC, Ingbar SH. Hyperthyroidism as a late sequela in patients with
Graves’ disease treated with antithyroid agents. J Clin Invest 1979;64:
1429-36.
6. Tamai H, Hirota Y, Kasagi, K. The mechanism of spontaneous
hypothyroidism in patients with Graves’ disease after antithyroid drug
treatment. J Clin Endocrinol Metab 1987;64: 718-22.
7. Hamada N, Ito K, Mimura T. Retrospective revaluation of the
significance of thyroid microsomal antibody in the treatment of Graves’
disease. Acta Endocrinol (Copenh.) 1987;114: 328-35.
8. Romaldini JH, Bromberg N, Werner RS. Comparison of effects of high
and low dosage regimens of antithyroid drugs in the management of
Graves’ hyperthyroidism. J Clin Endocrinol Metab 1983;57: 563-70.
9. Irvine WJ, Macgregor AG, Stuart AE. The prognostic significance of
thyroid antibodies in the management of thyrotoxicosis. Lancet 1962;2:
843-7.
10. Takaichi Y, Tamai H, Honda K et al. The significance of
antithyroglobulin and anti thyroidal microsomal antibodies in patients
with hyperthyroidism due to Graves’ disease treated with antithyroidal
drugs. J Clin Endocrinol Metab 1989;68: 1097-00.
11. Khoury EL, Haminond L, Bottayyo GF, et al. Presence of the organ
specific microsomal autoantigen on the surface of human thyroid cells
in culture: its involvement in complement-maliated cytotoxicity. Clin
Exp Immunol 1981;45: 316- 28.
12. Bagnur U, Schlcvsener H, Wall Jr. Antibody dependent cell-mediated
cytotoxicity against human thyroid cells in Hashimoto’s thyroiditis but
not Graves’ Disease. J Clin Endocrin Metab 1984;59: 734-38.
13. Wasserman J, Stedingk von LV, Perlmann P, Johnson J. Antibody
induced in vitro lymphocyte cytotoxicity in Hashimoto’s thyroiditis. Int
Arch Allergy 1974;47:473-82.
14. Dessaint JP, Wattre P, Wemeau JL, et al. Antibody inducing lymphocyte
cytotoxicity and lymphocyte-mediated cytotoxicity in autoimmune
thyroid disease. Pathol Biol 1981;29: 211-15.
13
REVIEW ARTICLE

Iodine supplementation: Benefits vs Concerns

Gopalakrishnan Sripathy, Marwaha Raman Kumar

Department of Endocrinology & Thyroid Research Centre, Institute of Nuclear Medicine and Allied Sciences, Delhi, India

ABSTRACT

IDD encompasses a broad spectrum which includes neurologic cretinism, physical/mental retardation in childhood, goitre
and reduced cognitive function and work output.Observational studies on populations and experimental studies have
suggested iodine deficiency to be the underlying basis for endemic goitre as well as endemic cretinism. The diagnosis of IDD
is made at the level of community and cannot be made at level of individual. Though presence of goitre and cretinism are
indicative of iodine deficiency in the community, objective methods are necessary to assess prevalence and severity of iodine
deficiency due to the fact that IDD often exists with subtler manifestations. Agencies such as the World Health Organization
(WHO), the International Council for Control of Iodine Deficiency Disorders (ICCIDD) and the UNICEF jointly
proposed various indicators to estimate prevalence of IDD and assess the impact of iodine prophylaxis. Goitre survey remains
the most important tool to measure iodine deficiency and estimate the population at risk. In 1999 that nearly 38% of world
population spread across 130 countries were affected by IDD making IDD the most common endocrine disorders world
wide. The recommended daily dietary intake of iodine varies from 50mg in infant, to 150mg in adult and 200mg during
pregnancy and lactation. Provision of iodine in diet is achieved by either universal salt iodisation (USI) or iodized oil as
injectable/oral formulations. Despite all the above adverse effects of iodisation reported so far, these have not been found to
have major consequences to public health. The safety of iodated salt as the public health approach to eliminate IDD is well
known. Benefits of correcting iodine deficiency far outweigh its risks. Iodine induced thyrotoxicosis and other adverse
effects can almost be entirely avoided by adequate iodine supplementation and sustained quality assurance and monitoring of
programs.[IJEM 2007;(3&4):15-21]
Key words: Iodine deficiency disorders, Iodine, ICCID, endemic goiter, iodine supplementation

INTRODUCTION deficiency in a community is termed ‘Iodine Deficiency

Synthesis of thyroid hormones in sufficient quantities
to meet the physiologic demands requires supply of adequate
amounts of exogenous iodine(1). It is estimated that a
minimum daily intake of 100µg iodine is essential to
eliminate all signs of iodine deficiency, though the daily
requirement varies between different age groups(2). While
iodine is required at all ages, the most critical stages of iodine
requirement are during fetal stage and early childhood due to
rapid neurological development which takes place at that
time. Deficiency of iodine will result in reduced formation of
thyroid hormones affecting growth, development and
metabolism of various tissues.
The spectrum of manifestations arising from iodine
Address for correspondence
Dr RK Marwaha, Division of Thyroid Research, INMAS, Brig. SK
Mazumdar Marg, Timarpur, Delhi-110054, India.
Tel: 011- 2393 9684, 011- 2393 4356, Fax: 011- 2391 9509
E-mail: marwaha_raman@hotmail.com
Disorders’ (IDD)(3). IDD encompasses a broad spectrum
which includes neurologic cretinism, physical/mental
retardation in childhood, goitre and reduced cognitive
function and work output. This term was coined to replace
‘endemic goitre’ which is the most visible manifestation but
underestimates the other subtle consequences in the iodine
deficient communities.
Epidemiology of IDD
Since diet is the sole source of iodine, its intake in
human and animal population is dependent on the iodine
content of water and soil(1). Land masses which were earlier
replete with iodine have been depleted of iodine due to
glaciations, rains, floods and repeated cultivation. As a result,
vast areas of earth’s land mass especially the mountainous
regions, rainy areas and previously glaciated regions of the
earth are depleted of iodine. In addition to the mountainous
regions, its deficiency has also been noted in lowlands and
plains of Asia, Africa and Europe(4-7). Observational studies

15
IJEM 2007;11(3 & 4):15-21
on populations and experimental studies have suggested
iodine deficiency to be the underlying basis for endemic
goitre as well as endemic cretinism. This is further supported
by the amelioration in IDD seen after iodine prophylaxis.
Thus, IDD constitute the most preventable cause of mental
retardation and remains a major public health problem
around the world.
IDD Assessment
The diagnosis of IDD is made at the level of
community and cannot be made at level of individual.
Though presence of goitre and cretinism are indicative of
iodine deficiency in the community, objective methods are
necessary to assess prevalence and severity of iodine
deficiency due to the fact that IDD often exists with subtler
manifestations. Agencies such as the World Health
Organization (WHO), the International Council for Control
of Iodine Deficiency Disorders (ICCIDD) and the UNICEF
(United Nations International Children’s Emergency Fund)
jointly proposed various indicators to estimate prevalence of
IDD and assess the impact of iodine prophylaxis(8). Goitre
survey remains the most important tool to measure iodine
deficiency and estimate the population at risk. Other
methods used in measuring IDD are: urinary iodine
excretion (UIE), thyroid size by ultrasonography (USG),
thyroid function tests and prevalence of cretinism.
Global Prevalence and burden of IDD
It was estimated in 1999 that nearly 38% of world
population spread across 130 countries were affected by
IDD(6) making IDD the most common endocrine disorders
world wide. Out of an estimated world population of 5.8
billion in different regions, 3.8% are estimated to be suffering
from iodine deficiency in some form, though only 12% is
affected by goitre. In 1994, 43 million were thought to be
suffering from some degree of mental handicap as a result of
IDD(8). It is known that severe deficiency of iodine exists in
most of developing countries and mild to moderate ID exists
in parts of Europe though accurate data on global prevalence
is lacking.
Iodine prophylaxis and supplementation
The recommended daily dietary intake of iodine varies
from 50ug in infant, to 150mg in adult and 200mg during
pregnancy and lactation(2). Provision of iodine in diet is
achieved by either universal salt iodisation (USI) or iodized
oil as injectable/oral formulations(9). While USI achieves
gradual elimination of IDD in whole population, iodized oil
delivery through primary health care systems can have rapid
impact in select target populations like children/pregnant
woman.
Evolution of iodisation programs
Switzerland and the United States of America (USA)
were among the first countries to launch iodisation programs
in 1920s. This was done subsequent to recognizing the high
prevalence of goitre and cretinism by surveys and the benefit
of iodisation by experimental studies(9). Salt iodisation along
16
with introduction of iodate and iodophores in food industry
helped achieve sufficient iodine nutrition in most North
American and North European countries(10). Experimental
studies were carried out in several countries such as Papua
New Guinea, India and others. The positive outcomes from
these subsequently triggered launch of widespread
campaigns for iodine supplementation around the
world(11).
The goal to eliminate IDD from around the globe by
the year 2000 was adopted by the World Summit for Children
in 1990(6). In its latest recommendation by WHO/
UNICEF/ICCIDD, salt iodisation at production site is
targeted in the range of 20-40 mg iodine/kg of salt so as to
provide the daily requirements of iodine in the adult of about
150µg/d(12). Global campaigns for salt iodisation has
achieved remarkable success so much, that by 1995, of 94
countries that had UNICEF programs, 58 had achieved the
goal of iodization of 90% edible salt(13). The present article
aims to review the benefits achieved vis-à-vis some unwanted
effects observed during iodine supplementation programs.
Iodine supplementation - benefits
World scenario: Goitre prevalence and UIE
Subsequent to the first experiments with introduction
of iodine in diet of local populations in Switzerland, studies
showed regression of goitre, reduction in goitre prevalence,
increase in average height of children, reduction in incidence
of deaf-mutism and prevention of cretinism(14). Similar
iodisation program undertaken in USA resulted in total
elimination of endemic goitre(15). A recent study conducted
4 years after iodised salt prophylaxis in Cote d’Ivoire,
Switzerland found reduction in mean thyroid size (56%),
goitre rate (52 to 19%) and normalization of median UIE in
children(16).
World scenario: Pregnancy outcomes and offspring
Several studies were conducted on pregnant women
and their offspring in various countries after the women were
supplemented with iodine in the form of iodized oil
injections. Neonatal outcomes improved and prevalence of
goitre and cretinism decreased in Papua New Guinea(17,18).
Long term studies in the progeny also showed improvement
in the cognitive and motor functions: tests like grip strength,
speed of movement, unimanual or bimanual accuracy were
performed better by the children in the supplemented group
than from control women. There was a salutary effect of
iodine supplementation in children born to mothers in terms
of school attainments and neuropsychological testing in
Ecuador(19, 20).
In Zaire, pregnancy outcomes such as birth weight,
incidence of infantile chemical hypothyroidism, reduction in
perinatal mortality and development quotients of offspring
were better in iodine supplemented group as compared to
controls(21). The beneficial effects noted in these studies
were instrumental in persuading most of countries in
Europe, Latin America and South East Asia to work towards
IDD elimination by iodine supplementation(9).
Iodine supplementation............................
Indian scenario
The early reports pointed to the presence of endemic
goitre and cretinism in the Himalayan belt and Gangetic
plains of Uttar Pradesh(22,23,24). The first evidence to show
that iodised salt as an effective approach to iodine
supplementation came from the results of an experimental
study in the Kangra valley between 1956 and 1972(25,26).
This group found that goitre prevalence reduced from 35% to
15% in 6 years and to 9% after 12 years of use of iodised salt in
the community. This gave the impetus for launching of
national goitre control program in 1962, with iodised salt as
the major route to provide iodine.
A nationwide study undertaken by the Indian Council
of Medical Research (ICMR) found IDD to be endemic in
235 out of 275 districts surveyed and it was estimated that
nearly 100 million of the Indian population is at risk of
IDD(27). Considering the widespread presence of IDD and
the gravity of the problem, National Goitre Control Program
(1962) was re-designated as National Iodine Deficiency
Disorders Control Program (NIDDCP) in 1992 with
adoption of universal salt iodisation as its main strategy for
control and sustained elimination of IDD.
While USI gained wide acceptance with the medical
community, iodized oil injections did not find favour except
for an experimental study which used iodized oil in two
districts of UP(28). Regardless of the approach used for
iodine supplementation, studies showed benefits in terms of
improvement in UIE and reduction in goitre prevalence.
Most of studies that have evaluated the impact of
universal salt iodisation have relied on goitre prevalence and
urinary iodine excretion (UIE) as indicators. Studies from
Delhi as well as other regions of the country revealed
adequate median UIE in school children(29,30,31). Goitre
prevalence (GP) has also been shown to be declining in the
country, as for example in Delhi, the GP reduced from 55% in
1983 to 19% and 9.2% in later studies(30, 31).
Following the USI campaign, there has been significant
improvement in iodine nutrition in terms of UIE and iodine
content of salt(31,32). There is also indirect evidence of
better iodine nutrition in terms of reduction in size of the
gland in terms of goitre grade with more than 90% goiters
seen in surveys to be of grade 1(29,30). The prevalence of
thyroid nodules is also low (0.04%), though pre-iodisation
data is not available in this regard. Similarly, two recent
studies, one in pregnant women and another in children
showed iodine sufficiency(33,34).
The effect of iodine deficiency on neurodevelopment
was shown by Kochupillai et al when they found that 56% of
schoolchildren in iodine deficient villages of this country had
intelligence quotient (IQ) less than 80 compared to 9% in
non-endemic areas(35,36). It was also seen that more than
80% of children in endemic villages had IQ less than 90.
Follow up studies after iodisation program clearly revealed
drastic improvement in IQ as shown in table 1 (personal
communication- Prof Manju Mehta).
Gopalakrishnan S et al
Table 1: Comparison of intelligence quotient (MISIC) in school
going children from District Gonda, Uttar Pradesh, India
IQ distribution expressed as percentage
< 69 70-79 80-89 90-109 110-119 >120
Year 2001
(n = 60) - 8.3 16.7 51.7 18.3 5
Year 1986
( n= 60) 23.3 33.3 25 16.7 1.7 0
(Courtesy: Prof. Manju Mehta, AIIMS, New Delhi)
All these studies are indicative of widespread benefits as
well as remarkable success in the nationwide iodisation being
pursued under the National Iodine Deficiency Disorders
control programme by the Government of India.
Iodine supplementation – concerns
Though supplementation of iodine is associated with
large scale benefits, concerns have been raised regarding side
effects due to the complex nature in which different levels of
iodine act on thyroid gland. Though evidence from studies
show that iodine intake up to 1mg/day could be tolerated by
normal adults(37,38), this was not reassuring enough due to
accumulation of evidence to the contrary. Continued
exposure to iodine at levels higher than required daily intake
may result in clinical conditions like goitre, hypothyroidism,
autoimmunity and others. (It is thought that these are more
likely to occur during iodine supplementation in iodine
deficient populations).
Thyrotoxicosis
Iodine induced thyrotoxicosis (IIT) was first reported
from Tasmania and has since been observed in most of
iodisation programs(39,40). The outbreak occurred in
Tasmania following iodine supplementation by iodine
tablets, iodized bread and use of iodophores in the milk
industry. The incidence increased from 24/100,000 in 1963 to
125/100,000 in 1967 and occurred more frequently in people
over 40 years of age and those with multi-nodular goiters.
Epidemic lasted for 10-12 years, after which incidence of
thyrotoxicosis fell below that prior to the epidemic despite
continued iodisation.
A sharp increase in incidence of thyrotoxicosis from
3/100,000 to 7/100,000 was observed in Zimbabwe over 18
months of introduction of iodised salt(41). High risk of
iodine induced hyperthyroidism was also reported from
Kivu, Zaire following iodised salt introduction(42). A multi-
centric study in 7 African countries including Congo and
Zimbabwe showed that thyrotoxicosis stemmed from
sudden induction of excessively iodised salt in severely iodine
deficient population for a long time(43). In Switzerland, an
increase in incidence of thyrotoxicosis by 27% was seen
during the year after level of iodine supplementation was
increased from 90µg/day to 150µg/day(44). Similarly,
introduction of iodised salt in China with borderline
deficiency resulted in slight but significant increase in the
incidence of thyrotoxicosis(45).
17
IJEM 2007;11(3 & 4):15-21
In variance to the above reports, two controlled studies
using iodized oil in iodine deficient population of Iran, and
Romania did not find any increase in incidence of IIT while
goitre prevalence decreased(46, 47, 48). A recent study from
three provinces of China with mild iodine deficiency (UIE
84 µg/lit, Panshan), more than adequate iodine intake (243
µg/lit, Zhangwa) and excessive iodine intake(651 µg/lit,
Huanghwa) respectively showed no association of increase in
iodine with hyperthyroidism(49). Other studies did not
reveal any excess occurrence of hyperthyroidism after iodine
prophylaxis (50,51). Study on thyroid function during goiter
surveys in India also did not show hyperthyroidism though
the country is undergoing iodisation for last two
decades(30, 51).
It appears that while benefits of iodisation are
overwhelming, it could result in IIT especially in the early
phase, in individuals with pre existing nodular disease, in the
absence of adequate monitoring of the programs.
Goitre and autoimmunity
It has been suggested that iodine supplementation
could induce/aggravate autoimmunity resulting in goitre and
thyroid dysfunction as evident from animal studies,
experimental studies on humans and population studies. The
first observations were made in chicken and rats when
experimental autoimmune thyroiditis (EAT) was induced on
administration of iodine(52, 53). This hypothesis was further
supported by population studies from USA and Japan which
showed higher prevalence of AIT in parallel with higher
iodine intake(54,55,56). Iodinated contrast agents and
amiodarone which contain large amounts of iodine are also
reported to induce AIT in certain individuals(57).
Lymphocytic infiltration of thyroid gland and
development of antithyroid antibodies in serum were
reported following iodisation programs in countries such as
USA, Greece(58,59). Increased production of anti-thyroid
antibodies in association with increase in iodine intake was
first reported after introduction of iodised oil in Greece and
Italy (60,61). In Epirus which was under salt iodisation for 3
decades, overall prevalence of AIT by thyroid antibodies was
3.3% & goitre specific prevalence was 16.5%(62).
A study on schoolchildren from Delhi, India found
autoimmune thyroiditis (positive anti-microsomal or anti-
thyroglobulin or both) in 112 of 396 goitrous subjects out of
4320 children(30). This study also reported direct correlation
between urinary iodine excretion (UIE) and autoimmunity
with goitre and autoimmunity with thyroid dysfunction
(subclinical hypothyroidism). In China, autoimmune
thyroiditis was found to be associated with more than
adequate or excess iodine but no such relation of iodine status
with thyroid antibodies alone(49).
Though rising incidence of thyroid autoimmunity is
reported by above studies, other studies using iodine have
failed to find similar evidence(63). Two population studies
from India and studies from iodine deficient and replete areas
of Europe did not show any correlation between UIE and
18
thyroid autoimmunity(51, 64, 65, 66). A one year prospective
trial in Northern Morocco following introduction of iodised
salt showed a transient increase in anti-thyroglobulin
antibodies but the antibody levels returned to baseline after 1
year(67). Similar findings were reported from Sri Lanka but
pre-iodisation status was unknown(68).
Iodine nutrition and thyroid dysfunction
Some studies point to increasing thyroid dysfunction
with increased iodine intake possibly due to iodine directly
suppressing thyroid function as well as iodine inducing
autoimmune thyroiditis. A recent study from three different
regions of China with differing iodine intake, increased
iodine intake was associated with increase in prevalence of
overt and subclinical hypothyroidism(49). The cumulative
incidence of supranormal thyrotropin (TSH) among
euthyroid subjects with positive antithyroid antibodies
increased with increasing iodine intake in all the three
cohorts(49). In another study on children from Delhi, the
median UIE in children with subclinical hypothyroidism
(17.6 ± 3.4 µg/dl) was significantly higher than in euthyroid
children with autoimmune thyroiditis (14.7 ± 4.4; p <
0.001)(30). High prevalence of raised TSH (>5 µIU/l) in
32.4% seen 3 years after introduction of iodised salt in Car
Nicobar Islands in Bay of Bengal (69 mallik).
Other studies do not corroborate the above evidence
linking iodine with thyroid dysfunction. In United States,
National Health and Nutrition Evaluation Survey
(NHANES III) did not find any correlation between UIE
and thyroxine (T4) or TSH(10). Similarly, one countrywide
study from India also did not show any correlation between
urinary iodine and thyroid function(29, 51).
Iodine nutrition and goiter
It is suggested that excessive iodine could cause goitre
due to iodine induced increase in autoimmune thyroiditis as
well as iodine induced block of thyroid hormone release
causing increase in TSH and goitre. Higher median urinary
iodine was shown in goitrous subjects compared to controls
in a cross sectional study of school children in India(29). In
Delhi, India direct correlation of UIE with goitre was seen in
presence of autoimmune thyroiditis but not otherwise(30). A
large prospective study from China showed goitre
correlation with mild iodine deficiency as well as excess
iodine intake(49). A large international study showed direct
relation of urinary iodine >50µg/dl with thyroid volume but
not for 30-50 µg/dl range(70).
Iodine and thyroid neoplasia
The existence of a relationship between occurrence of
thyroid cancer and iodine status continues to be debated. In
experimental studies on iodine deficient animals, increased
development of thyroid carcinomas was seen(71,72). It was
proposed that chronic stimulation due to raised TSH seen in
such animals may induce neoplasia in thyroid, but whether
this could play a role in areas of endemic goitre is not clear.
The overall incidence of thyroid carcinoma in a
population is not thought to be influenced by iodine
Iodine supplementation............................
intake(73). In Italy, incidence of thyroid carcinoma was
higher in an iodine-deficient area compared to that in an
iodine-sufficient region(74). On the other hand, studies
from Iceland and Hawaii which are areas of high iodine
intake, the incidence was initially linked to iodine intake, but
this could also be due to higher natural radiation in these
volcanic areas (75,76). Reduction in incidence of thyroid
cancer from 2-3/100,000 in 1950 to 1-2/100,000 in 1998 was
seen in Switzerland, after iodine supplementation(77).
Similarly, after iodine prophylaxis in Poland, fine needle
aspiration of 3572 patients over a period of 15 years (1985-
1999) found significant decrease in neoplastic lesions and
increase in ratio of papillary to follicular carcinoma(78).
There is a distinct change in the type of carcinomas in
thyroid gland following iodisation in deficient populations.
The ratio of papillary to follicular carcinomas rose in
Argentina and Switzerland(79,80). These studies and others
denote changes in epidemiological pattern of thyroid cancer
subsequent to iodine prophylaxis, with probable
improvement in prognosis due to shift towards more
differentiated forms of thyroid cancer that are diagnosed at
earlier stages(81).
Data on this aspect is scanty from India with one study
reporting that course and outcome of differentiated thyroid
cancer in children from iodine deficiency areas is no different
from those in iodine sufficient areas(82).
SUMMARY OF EVIDENCE AND
CONCLUSIONS
Despite all the above adverse effects of iodisation
reported so far, these have not been found to have major
consequences to public health. The safety of iodated salt as
the public health approach to eliminate IDD is well known.
Benefits of correcting iodine deficiency far outweigh its risks.
Iodine induced thyrotoxicosis and other adverse effects can
almost be entirely avoided by adequate iodine supplemen-
tation and sustained quality assurance and monitoring of
programs.
REFERENCES
1. Larsen PR, Davies TF, Schlumberger MJ, Hay ID. Thyroid
Physiology & diagnostic evaluation of patients with thyroid disorders.
In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS (eds)
Williams Textbook of endocrinology, 10th edition. Philadelphia,
Saunders, 2002 p331-373.
2. National Research Council. Recommended dietary allowances, 10th
ed. Washington DC, National Academy of Sciences, 1989.
3. Hetzel BS. The story of iodine deficiency: an international challenge
in nutrition. Oxford university press, Delhi. 1989.
4. Stanbury JB, Hetzel BS. Endemic goiter and cretinism: iodine
nutrition in health and disease. New York, John Wiley and Sons,
1980. p1-606.
5. Hetzel BS, Dunn JT, Stanbury JB. The prevention and control of
iodine deficiency disorders. Amsterdam, Elsevier Science,1987. p 1-
354.
6. WHO/UNICEF/ICCIDD. Progress towards the elimination of
Gopalakrishnan S et al
iodine deficiency disorders(IDD). Geneva:World Health
Organization;1999. Publication WHO/NHD/99.4:1-33.
7. Koutras DA, Matovinovic J, CVought R. The ecology of iodine. In:
Stanbury JB, Hetzel BS eds. Endemic goiter and endemic cretinism.
New York, JohnWiley and Sons,1980. p185-95.
8. WHO/UNICEF/ICCIDD. Indicators for assessing iodine deficiency
disorders and their control through salt iodization. Geneva: World
Health Organization:1994.Publication WHO/NUT/94.6.
9. Hetzel B S. Recent progress in the elimination of Iodine deficiency
disorders. In: Hetzel B S, Pandav C S. S.O.S for a billion, The
conquest of iodine deficiency disorders. Delhi, Oxford University
press, 1996, page 31-56.
10. Soldin OP, Tractenberg RE, Pezzullo JC. Do thyroxine and thyroid-
stimulating hormone levels reflect urinary iodine concentrations?
Ther Drug Monit. 2005;27: 178-85.
11. Delange F M, Dunn J T. Iodine deficiency. In: Braverman L E, Utiger
R D. (eds) Werner & Ingbar’s The Thyroid, A fundamental and
clinical text, 9th edition, Philadelphia, Lippincott, Williams & Wilkins
2004, p 204-305.
12. WHO/UNICEF/ICCIDD. Recommended iodine levels in salt and
guidelines for monitoring their adequacy and effectiveness. Geneva:
World Health Organization; 1996. WHO/NUT/96.13: 1-9.
13. UNICEF. The progress of nations. New York: United Nations
Children’s Fund; 1995:1-54.
14. Burgi H, Supersaxo Z, Selz B. Iodine deficiency diseases in
Switzerland one hundred years after Theodor Kocher’s survey: A
historical review with some new goitre prevalence data. Acta
Endocrinologica (Copenh) 1990; 123: 577-90.
15. Marine D, Kimball OP. The prevention of simple goitre in man. Am J
Med Sci 1922: 163-634.
16. Zimmermann MB, Hess SY, Adou P, Toresanni T, Wegmiller R,
Hurreli R F. Thyroid size and goitre prevalence after introduction of
iodized salt: a 5 year prospective study in schoolchildren in Cote
d’Ivoire. Am J Clin Nutr 2003 ;77: 663-7.
17. Pharoah POD, Buttifield IH, Hetzel BS. The effect of iodine
prophylaxis on the incidence of endemic cretinism. In: Stanbury JB,
Kros RL eds. Human Development and the thyroid gland; Relation
to endemic cretinism. New York, Plenum Press, 1972; 201.
18. Pharoah POD, Buttifield IH, Hetzel BS. Neurological damage to the
foetus resulting from severe iodine deficiency during pregnancy.
Lancet 1971;i: 308-10.
19. Pharoah POD, Connolly KJ. A controlled trial of iodinated oil for the
prevention of endemic cretinism. A long term follow up. Int J
Epidemiol 1987;16: 68-73.
20. Fierro-Benitez R, Cesar R, Stanbury JB, Rodrigouez P, Garces F,
Fierro-Renoz F, et al. Effects on schoolchildren of prophylaxis of
mothers with iodized oil in an area of iodine deficieny. J Endocrinol
Inv 1988;11: 327-35.
21. Thilly CH, Lagasse R, Bourdoux P, Ermans AM. High dose iodine
prophylaxis in severe endemic goitre. A balance of risks. J Mol Med
1980;4: 191-7.
22. McCarrison R, Newcomb C, Viswanath B, Norris RV. Ind J Med Res
1927;15: 207.
23. Stott H, Bhatia BB, Lal RS, Rai KC. Ind J Med Res 1931 ; 18 : 1059
24. Ramalingaswami V, Subramanian TAV, Deo MG. The aetiology of
Himalayan endemic goitre. Lancet 1961;1: 791-4.
25. Sooch SS, Ramalingaswami V. Preliminary report of an experiment in
the Kangra valley for the prevention of Himalayan endemic goitre
with iodized salt. Bull World Health Organ 1965;32: 299-315.
26. Sooch SS, Deo MG, Karmarkar MG, Kochupillai N, Ramachandran
K, Ramalingaswami V. Prevention of endemic goitre with iodised salt.
Bull World Health Organ 1973;49: 307-12.
19
IJEM 2007;11(3 & 4):15-21
27. Indian Council of Medical Research. Epidemiological survey of
endemic goitre and endemic cretinism. An ICMR task force study.
ICMR, New Delhi, 1989.
28. Sankar R, Pandav CS, Ahmed FU, Rao P, Dwivedi MP, Desai V, et al.
Review of experiences with iodized oil in national programmes for
control of Iodine Deficiency Disorders. Ind J Pediatr 1995;62: 381-
93.
29. Marwaha RK, Tandon N, Gupta N, Karak AK, Verma K, Kochupillai
N. Residual goitre in the postiodization phase: iodine status ,
thiocyanate exposure and autoimmunity. Clin Endocrinol (Oxf)
2003;59: 672-81.
30. Gopalakrishan S, Singh SP, Prasad WR, Jain SK, Ambardar VK,
Sankar R. Prevalence of goitre and autoimmune thyroiditis in
schoolchildren in Delhi, India, after two decades of salt iodisation. J
Pediatr Endocrinol Metab 2006;19: 889-93.
31. Pandav CS, Mallik A, Anand K, Pandav S, Karmarkar MG. Prevalence
of iodine deficiency disorders among schoolchildren of Delhi. Natl
Med J Ind 1997;10: 112-4.
32. Kapil U, Sethi V, Goindi G, Pathak P, Singh P. Elimination of iodine
deficiency disorders in Delhi. Ind J Pediatr 2004;71: 211-2.
33. Chakraborty I, Chatterjee S, Bhadra D, Mukhopadhyaya BB,
Dasgupta A, Purkait B. Iodine deficiency disorders among the
pregnant women in a rural hospital of West Bengal. Ind J Med Res
2006 ; 123 : 825-9
34. Sivakumar B, Nair KM, Sreeramulu D, Suryanarayana P, Ravinder P,
Shatrugna V, et al. Effect of micronutrient supplement on health and
nutritional status of schoolchildren: biochemical status. Nutrition.
2006;22(1Suppl): S15-25.
35. Kochupillai N, Pandav CS, Godbole MM, Ahuja MMS. Bul WHO
1986;64: 547-51.
36. Kochupillai N, Pandav CS. In: Hetzel BS, Stanbury JB (eds).
Prevention and control of iodine deficiency disorders. New York,
Elsevier, 1984. p 203-12.
37. Thomson CD. Dietary recommendations of iodine around the
world. IDD Newsletter 2002;18: 38-42.
38. WHO. Iodine and health, eliminating iodine deficiency disorders
safely through salt iodization. World Health Organization, Geneva,
1994, p 1-7,
39. Stanbury JB, Ermans AE, Bordoux P, Todd C, Oken E, Tonglet R, et al.
Iodine-induced hyperthyroidism: occurrence and epidemiology.
Thyroid 1998;8: 83-100.
40. Connolly RJ, Vidor GI, Stewart JC. Increase in thyrotoxicosis in
endemic goitre area after iodation of bread. Lancet 1970;1(7645):
500-2
41. Todd CH, Allain T, Gomo ZA, Hasler JA, Ndiweni M, Oken E.
Increase in thyrotoxicosis associated with iodine supplements in
Zimbabwe. Lancet 1995;346: 1563-4.
42. Bourdoux P, Ermans AM, Mukalay WA, Mukalay A, Filetti S,
Vigneri R. Iodine-induced thyrotoxicosis in Kivu, Zaire. Lancet
1996;347: 552-3.
43. Delange F, de Benoist B, Alnwick D. Risks of iodine-induced
hyperthyroidism after correction of iodine deficiency by iodized salt.
Thyroid 1999;9: 545-56.
44. Baltisberger BL, Minder CE, Bürgi H. Decrease of incidence of toxic
nodular goitre in a region of Switzerland after full correction of mild
iodine deficiency. Eur J Endocrinol 1995;132: 546-9 .
45. Yang F, Teng W, Shan Z, Guan H, Li Y, Jin Y, et al. Epidemiological
survey on the relationship between different iodine intakes and the
prevalence of hyperthyroidism. Eur J Endocrinol 2002;146: 613-8.
46. Azizi F, Daftarian N. Side-effects of iodized oil administration in
patients with simple goiter. J Endocrinol Invest 2001;24: 72-7.
20
47. Mirmiran P, Kimiagar M, Azizi F. Three-year survey of effects of
iodized oil injection in schoolchildren with iodine deficiency
disorders. Exp Clin Endocrinol Diabetes 2002;110: 393-7.
48. Simescu M, Varciu M, Nicolaescu E, Gnat D, Podoba J, Mihaescu M,
et al. Iodized oil as a complement to iodized salt in schoolchildren in
endemic goiter in Romania. Horm Res 2002;58: 78-82.
49. Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, et al. Effect of iodine
intake on thyroid diseases in China. N Engl J Med 2006; 354: 2783-
93.
50. García-Mayor RV, Ríos M, Fluiters E, Méndez LF, García-Mayor EG,
Andrade A. Effect of iodine supplementation on a pediatric
population with mild iodine deficiency. Thyroid 1999;9: 1089-93.
51. Marwaha RK, Tandon N, Gupta N, Karak AK, Verma K, Kochupillai
N. Residual goitre in the postiodization phase: iodine status,
thiocyanate exposure and autoimmunity. Clin Endocrinol (Oxf).
2003;59: 672-81.
52. Bagchi N, Brown TR, Urdanivia E, Sundick RS. Induction of AIT in
chickens by dietary iodine. Science 1985;230: 325-327.
53. Allen EM, Appel MC, Braverman LE. Iodine-induced thyroiditis and
hypothyroidism in the hemithyroidectomized BB/W rat.
Endocrinology 1987;121: 481-5.
54. Laurberg P. Iodine intake - what are we aiming at?. J Clin Endocrinol
Metab 1994;79: 17-9.
55. Hall R, Lazarus JH. Changing iodine intake and the effect on thyroid
disease. Br Med J 1987;294: 721-2.
56. Inoue M, Taketani N, Sato T,Nakajima H. High incidence of chronic
lymphocytic thyroiditis in apparently healthy schoolchildren:
epidemiological and clinical study. Endocrinol Jpn 1975;22: 483-8.
57. Martino E, Bartalena L, Bogazzi F, Braverman LE. The effects of
amiodarone on the thyroid. Endocr Rev 2001;22: 240-54.
58. McConahey WM, Keating FR, Beahr OH et al. On the increasing
occurrence of Hashimoto’s thyroiditis. J Clin Endocrinol Metab
1962;22: 542-4.
59. Kahaly GJ, Dienes HP, Beyer J, Hommel G. Iodide induces thyroid
autoimmunity in patients with endemic goitre: a randomised double-
blind, placebo-controlled trial. Eur J Endocrinol 1998;139: 290-7.
60. Boukis MA, Koutras DA, Souvatzoglou A, Evangelopoulou A,
Vrontakis M, Moulopoulos SD. Thyroid hormone and
immunological studies in endemic goitre. J Clin Endocrinol Metab
1983;57: 859-62.
61. Fenzi GF, Giani C, Ceccarelli P, Bartalena L, Macchia E, Aghini-
Lombardi F, et al. Role of autoimmune and familial factors in goiter
prevalence. Studies performed in a moderately endemic area. J
Endocrinol Inv 1986;9: 161-4.
62. Tsatsoulis A, Johnson EO et al. Thyroid autoimmunity is associated
with higher urinary iodine concentrations in an iodine-deficient area
of Northwestern Greece. Thyroid 1999;9: 279-83.
63. Knobel M, Medeiros-Neto G. Iodized oil treatment for endemic
goitre does not induce surge of positive serum concentrations of anti-
thyroglobulin or anti-microsomal autoantibodies. J Endocrinol Inv
1986;9: 321-4.
64. Marwaha RK, Tandon N, Karak AK, Gupta N, Verma K, Kochupillai
N. Hashimoto’s thyroiditis: countrywide screening of goitrous
healthy young girls in post-iodization phase in India. J Clin
Endocrinol Metab 2000;85: 3798-802.
65. Loviselli A, Velluzzi F, Mossa P, Cambosu MA, Secci G, Atzeni F, et al.
Sardinian School children Study Group. The Sardinian
Autoimmunity Study: 3. Studies on circulating antithyroid
antibodies in Sardinian schoolchildren: relationship to goiter
prevalence and thyroid function. Thyroid 2001;11(9): 849-57.
66. Kabelitz, M, Liesenkotter KP, Stach B, Willgerodt H, Stablein W,
Iodine supplementation............................
Singendonk W, et al. The prevalence of antithyroid peroxidase
antibodies and autoimmune thyroiditis in children and adolescents in
an iodine replete area. Eur J Endocrinol 2003;148(3): 301-7.
67. Zimmermann MB, Moretti D, Chaouki N, Torresani T.
Introduction of iodized salt to severely iodine-deficient children does
not provoke thyroid autoimmunity: a one-year prospective trial in
northern Morocco. Thyroid 2003;13(2): 199-203.
68. Mazziotti G, Premawardhana LD, Parkes AB, Adams H, Smyth PP,
Smith DF, et al. Evaluation of thyroid autoimmunity during iodine
prophylaxis-the Sri Lankan experience. Eur J Endocrinol 2003;
149(2): 103-10.
69. Mallik AK, Pandav CS, Achar DP, Anand K, Lobo J, Karmarkar MG, et
al. Iodine deficiency disorders in Car Nicobar (Andaman and
Nicobar Islands). Natl Med J India 1998 ;11: 9-11.
70. Zimmermann MR, Ito Y, Hess SY, Fujieda K, Molinari L. High
thyroid volume in children with excess dietary iodine. Am J Clin
Nutr 2005;81: 840-4.
71. Schaller RT, Stevenson JK. Development of carcinoma of the thyroid
in iodine-deficient mice. Cancer 1966;19: 1063-80.
72. Fortner JG, George PA, Sternberg SS. Induced and spontaneous
thyroid cancer in the Syrian (golden) hamster. Endocrinology 1960;
66: 364-76.
73. Kaplan MM, ed. Thyroid carcinoma. Endocrinol Metab Clin North
Am 1990;19: 469-766.
74. Belfiore A, La Rosa GL, La Porta GA, Giuffrida D, Milazzo G, Lupo L,
Gopalakrishnan S et al
et al. Cancer risk in patients with cold thyroid nodules: relevance of
iodine intake, sex, age and multinodularity. Am J Med 1992;93: 363-9.
75. Williams ED, Doniach I, Bjarnason O, Michie W. Thyroid cancer in
an iodide rich area: A histopathological study. Cancer 1977 ; 39 :
215-22.
76. Goodman MT, Yashizawa CN, Kolonel LN. Descriptive
epidemiology of thyroid cancer in Hawaii. Cancer 1988;61: 1272-81.
77. Levi F, Vecchia, CL, Randriamiharisoa A . Cancer mortality in
Switzerland 19889 Soz Preventimed 1991;36: 112-26.
78. Slowinska-Klencka D, Klencki M, Sporny S, Lewinski AI. Fine-
needle aspiration biopsy of the thyroid in an area of endemic goitre :
influence of restored sufficient iodine supplementation on the
clinical significance of cytologic results. Eur J Endocrinol 2002; 146:
19-26.
79. Harach HR, Escalante DA, Onativia A, Lederer Outes J, Saravia Day
E, et al.Thyroid carcinoma and thyroiditis in an endemic goitre region
before and after iodine prophylaxis. Acta Endocrinol (Copenh)
1985;108: 55-60.
80. Langsteger W, Koltringer P, Wolf G. The impact of geographical ,
clinical, dietary and radiation-induced features in epidemiology of
thyroid cancer. Eur J Cancer 1993;29A: 1547-53.
81. Feldt-Rasmussen U. Iodine and cancer. Thyroid 2001;11: 483-6.
82. Bal CS, Padhy AK, Kumar A. Clinical features of differentiated
thyroid carcinoma in children and adolescents from a sub-Himalayan
iodine-deficient endemic zone. Nucl Med Commun. 2001;22:
881-7.
21
REVIEW ARTICLE

Pheochromocytoma – revisited

Khursheed Alam Wani, Ajaz Ahmad Malik, Zahoor Ahmed Naikoo,

Department of General Surgery, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, J and K, India.

ABSTRACT

Pheochromocytomas are rare neuroendocrine tumours with a highly variable clinical presentation but most
commonly presenting with episodes of headaches, sweating, palpitations, and hypertension. The serious and
potentially lethal cardiovascular complications of these tumours are due to the potent effects of secreted
catecholamines. Biochemical testing for pheochromocytoma is indicated not only in symptomatic patients, but
also in patients with adrenal incidentalomas or identified genetic predispositions (eg, multiple endocrine
neoplasia type 2, von Hippel-Lindau syndrome, neurofibromatosis type 1, and mutations of the succinate
dehydrogenase genes). Imaging techniques such as CT or MRI and functional ligands such as 123I-MIBG are
used to localise biochemically proven tumours. After the use of appropriate preoperative treatment to block the
effects of secreted catecholamines, laparoscopic tumour removal is the preferred procedure. If removal of
pheochromocytoma is timely, prognosis is excellent. However, prognosis is poor in patients with metastases,
which especially occur in patients with large, extra-adrenal tumours. [IJEM 2007;(3&4):23-29]
Key words: Pheochromocytoma, catecholamines, VMA, MIBG, secondary hypertension

INTRODUCTION stomach and pancreas along left crus of diaphragm. Adrenal

Pheochromocytomas are rare catecholamine secreting glands are supplied by branches from inferior phrenic, aorta
tumours that if missed invariably prove fatal(1). These and renal artery. Right adrenal vein is short (3 mm) and drains
tumours arise from chromaffin cells derived from neural into inferior vena cava, rarely into right hepatic vein while as
crest tissue and appear brown on fixation with dichromate vein on left side empties into renal vein often after joining the
due to oxidation and polymerisation of catecholamines in the inferior phrenic.
storage granules. Most chromaffin cells degenerate after Adrenal mass
birth, largest collection is in the adrenal medulla (site for 85% Although majority of adrenal masses are benign,
cases of pheochromocytoma), rest of the tumours arise from malignant are not uncommon. Various types of adrenal
parasympathetic associated or sympathetic associated tumours are shown in table 1.
chromaffin tissue usually from collection of chromaffin
Table 1: Various adrenal tumours
tissue near the aortic bifurcation (organ of Zuckerkandl).
Less common sites are mediastinum (2%) and neck (1%)(1). I. Cortical tumors
Adenoma
Adrenal Gland Carcinoma
The adrenal glands are bilateral retroperitoneal organs Functional
Non-functional
located on the superior medial aspect of upper pole of each Myelolipoma
kidney weighing approximately 4 grams. The right adrenal is Adrenal oncocytoma
pyramid shaped, in relation to inferior vena cava and segment Non-functional
VII of liver, the left adrenal is flatter and lies posterior to Myelolipoma
Adrenal oncocytoma
Address for correspondence:
II. Medullary tumors
Dr. Ajaz Ahmad Malik
Pheochromocytoma
Department of General Surgery, Sher-i-Kashmir Institute of Medical
Neuroblastoma
Sciences, Srinagar, J and K, India.190011
Tele: 09419081332, e-mail: ajazamalik@yahoo.com; kalamwani2@rediffmail.com III. Others (including metastases)

23
IJEM 2007;11(3 & 4):23-29
Pheochromocytoma
The name pheochromocytoma proposed by Pick (1912)
is derived from Greek words phalo (dusky) and chroma
(colour). The first description of pheochromocytoma is
credited to Frenkel (1886) who reported bilateral tumour in
an 18 year old girl. Extra adrenal pheochromocytoma was
first reported by Alezais and Pevon (1908). Roux and Mayo
independently reported the first successful resection of
pheochromocytoma in 1926 and 1927 respectively. In 1929
Rabin reported excess of normal vasopressor agent in
pheochromocytoma. Epinephrine was isolated by Kelly and
colleagues (1936) while Holton (1949) demonstrated the
presence of norepinephrine in pheochromocytoma(2).
Pheochromocytoma accounts for approximately 0.05%-
0.1% of patients with any degree of hypertension(1). In
western population the prevalence of pheochromocytoma is
between 1:4500 and 1:1700 with an annual incidence of 8
cases per 1 million per year(3). The most common age group
affected is fourth and fifth decade with equal incidence in
both sexes. Significant numbers of pheochromocytomas
remain undiagnosed, first seen at autopsy and contribute to
the mortality in 60-75% of cases(4). It has been referred as
‘10% tumour’ (because 10% are malignant, bilateral, extra
adrenal, multiple, occur in children, familial) but recent
reports have challenged this concept with upto 24% being
familial(5).
Clinical features
Pheochromocytomas secrete excessive amounts of
catecholamines, dopamine, norepinephrine and
epinephrine; these also produce other hormones including
ACTH, calcitonin, somatostatin, oxytocin, vasopressin and
vasoactive intestinal peptide (VIP). The symptoms and signs
of pheochromocytoma (table 2) are due to these compounds
that are secreted(6).
Table 2: Symptoms and signs in pheochromocytoma
Symptoms Signs
Headache Hypertension
Palpitations Tachycardia/ reflex bradycardia
Sweating Postural hypotension
Anxiety/nervousness Weight loss
Tremulousness Pallor
Nausea/vomiting Hypermetabolism
Pain in chest Hyperglycemia
Weakness/fatigue Tremor
Dizziness Increased respiratory rate
The classical triad of symptoms include headache
(90%), palpitations and excessive generalised sweating
(60-70%)(1,6). Persistent hypertension is seen in only
50%(1). Differential diagnosis is given in table 3.
Approximately 75% deaths associated with untreated
pheochromocytomas are due to myocardial infarction or
cerebrovascular accident(4, 7).
24
Initial Biochemical Testing
Missing a pheochromocytoma can have deadly
consequences. Catecholamine secretion by pheochromo-
cytoma can be episodic or in patients who are asymptomatic,
negligible in nature so measurement of
Table 3: Differential diagnosis of pheochromocytoma (based on
symptoms)
Neuroblastoma/ganglioneuroma Paroxysmal tachycardia
Adrenal medullary hyperplasia Angina pectoris/ myocardial
infarction
Hyperadrenergic essential
hypertension Mitral valve prolapse
Baroreflex failure Aortic dissection
Thyrotoxicosis Hypoglycemia/ insulin reaction
Anxiety/panic attack Renal parenchymal/vascular disease
Migraine/cluster headache Intracranial lesions
Autonomic epilepsy Toxemia of pregnancy
Abrupt clonidine withdrawal Acute intermittent porphyria
Amphetamines/cocaine/
alcoholism Menopausal syndrome
catecholamine metabolites in initial screening is a better
practice as metanephrines are produced continuously within
pheochromocytoma cells independent of catecholamine
release, obviating the need for measurement during
hypertensive spells. Measurement of plasma-free
metanephrines and urinary fractionated metanephrine is the
most sensitive diagnostic test(8) followed by intermediate
sensitivity of urinary and plasma catecholamine levels,
whereas, urinary total metanephrines and VMA offered least
sensitivity(8). Spectrophotometric measurement of total
metanephrines has been replaced by newer chromatographic
methods that allow fractionated measurement of
normetanephrine and metanephrine (fractionated
metanephrines)(9). The urinary excretion or plasma
concentrations of metanephrines show strong correlation
with tumour size as compared to the catecholamine
level(10,11).
Sampling procedures
Blood should be collected with patient supine for 20
minutes before sampling. Patient should have refrained
from nicotine and alcohol for 12 hrs and preferably fasting
overnight. The sample is collected into tubes containing
heparin or ethylenediamine tetracetic acid (EDTA) stored in
ice at 4°C before centrifuge.
24 hour urine collection is preferred over blood
sampling as it avoids rigid sampling condition and is easy to
implement Urine collected is preserved in containers with 20
ml of 6N HCl or 25 ml of 50% acetic acid. For prolonged
storage, aliquots of blood or urine are stored at -80°C.
Pharmacologic tests
These are used to improve diagnostic accuracy for
pheochromocytoma. However provocative tests are
Pheochromocytoma - revisited................... KA Wani et al

inherently dangerous, suppression tests may be useful due to MRI (Figure 2)

low risk. MRI with or without gadolinium enhancement is a
Clonidine suppression test: Most often used suppression reliable method in identifying more than 95% of
test(12). Blood is drawn before and three hours after the oral tumours(17). It is superior to CT in assessment of
administration of clonidine 0.3 mg/70kg body weight, a relationship between the tumour and the surrounding
decrease of plasma levels of normetanephrine more than 40% vessels especially great vessels, rendering MRI important in
or to below upper reference limit has a diagnostic sensitivity ruling out vascular invasion(15,17). Chemical shift MRI
of 98% compared to 67% sensitivity for norepinephrine differentiates benign adenomas from pheochromocytoma,
alone(12). metastatic, hemorrhage psueudocysts or malignant tumours.
Glucagon is the safest and most specific of provocative On T2 sequence pheochromocytoma appears
tests(13) and can be used in patients receiving a- characteristically bright with high signal with no signal loss
blockers(13). It is given in a dose of 1mg intravenous bolus on opposed phase images due to hypervascularity(17). MRI is
and blood for plasma catecholamines drawn before and 2 a good imaging modality for detection of intracardiac,
minutes after drug is injected while monitoring blood juxtacardiac and juxtavascular pheochromocytoma because it
pressure & heart rate. An increase in plasma norepinephrine reduces cardiac and respiratory motion induced artifacts. The
of greater than three fold or to more than 2000 pg/ml is advantage MRI offers is lack of radiation exposure and it
considered a positive test(13). doesn’t cause release of catecholamines necessary but, MRI is
Localization costlier. MRI is the initial imaging for pheochromocytoma in
Attempt to locate a pheochromocytoma should only be pregnancy and in those who are allergic to contrast material
done after biochemical studies have established the presence used in CT(2).
of tumour. Overall pheochromocytoma in adrenal are more
easily identified than those at extra adrenal sites. For
localization two imaging studies one anatomical and one
functional should be performed to locate primary recurrent
or metastatic tumour.
CT scan
With or without contrast is the initial method used in
most institutions(Figure 1). It is easy, widely available and
relatively inexpensive. CT scan has 95% sensitivity and 70%
specificity in localizing adrenal tumours of 1 cm or more in
size and extra adrenal tumours of greater than 2 cm
size(14,15). Administration of intravenous contrast media
for CT scanning may evoke catecholamine release from
tumours, though iohexol has not been shown to cause any
hypertensive paroxysms(16). a-blockade prior to
administration of contrast agent is a precautionary measure.

Figure 2: MRI of abdomen with left adrenal pheochromocytoma

USG is not usually recommended except in case of

children and pregnant women when MRI is not available(2).
Functional Imaging
Functional imaging studies are performed as there is
presence of cell membrane and vesicular catecholamine
transport system in pheochromocytoma cells. Functional
imaging include 123I or 131I MIBG scintigraphy, 6-18F-
flourodopamine, 18F dihydroxyphenylalanine (18F-dopa),
11C-hydroxyephedrine and 11C-epinephine positron
emission tomography (PET).
MIBG
MIBG yields nearly 100% specificity for this
tumour(18). MIBG labeled with 131I has a false negative rate
Figure 1: CT scan of abdomen with right adrenal of 15% in patients with pheochromocytoma; MIBG labeled
pheochromocytoma
with 123I has much better sensitivity. Another advantage of 123I

25
IJEM 2007;11(3 & 4):23-29
over 131I labeled MIBG is the additional ability for imaging by
single photon emission computed tomography
(SPECT)(19) and also that 123I has shorter half life than 131I-
MIBG (13 hrs vs. 8.2 days) so higher doses can be given. I 131
can however be used as a modality of treatment in malignant
pheochromocytoma(19). In order to block uptake of free
123/131
I by thyroid gland , potassium iodide (100 mg twice a day)
for 4 days in 123I MIBG and for 7 days in 131I MIBG is given to
the patient. Patients are usually scanned at 24 hours and again
at either 48 or 72 hours to differentiate the images appearing
on earlier scan from being physiological or from tumour
(which persist or increase in later scans).
Positron Emission Tomography
PET imaging is done using short lived positron emitting
agents. Most PET radiopharmaceuticals used for detection of
pheochromocytoma enter the pheochromocytoma cells
using the cell membrane norepinephrine transporter.
Labeled analogue of dopamine is a useful scintigraphic agent
as dopamine is a better substrate for this transporter than
most other amines, including norepinephrine. 6-18F-
flurodopamine, sympathoneuronal imaging agent is a
positron emitting analogue of dopamine PET scan has been
shown to have 100% sensitivity(20) and is superior to 131I
MIBG scintigraphy in patients with metastatic
pheochromocytoma, with upto 100% sensitivity in most
cases(21).
Few cases of pheochromocytoma that are negative to
even 6-18F-flurodopmine PET scans have also been
identified, which were negative on 131I or 123I MIBG
scintigraphy also(2).
PET 11C-hydroxy ephedrine, 11C-epinephrine or
18F-flurodopa are other PET imaging agents. These agents
have limited diagnostic yield due to limited affinity for
norepinephrine transporter system and shorter half life of
11C radiopharmaceuticals (~20 minutes) rendering whole
body scans difficult(22).
Increased glucose metabolism characterizes various
malignant tumours and thus the uptake of glucose labeled
with 18F-fluroide is useful in imaging these tumours. FDG
PET reveals more metastasis than MIBG scintigraphy in
metastatic pheochromocytoma but it cannot distinguish
benign from malignant disease(23).
Advantages of PET scan is that it can be one within
minutes to hours after injecting a short lived positron
emitting agent. There is a low radiation exposure and a
superior spatial resolution cast limited availability of
radiopharmaceuticals and PET equipment are the drawbacks
for its widespread use.
Octreoscan
Somatostatin receptor scintigraphy using octreotide has
been used, its sensitivity is low especially in detecting solitary
tumour but octreoscan is useful in metastatic
pheochromocytoma especially those that express
somatostatin receptors and are negative on MIBG
26
scintigraphy and 6-18F-flurodopamine PET(24).
Other
Venacaval sampling for catecholamine and
metanephrines is done when extra adrenal tumour has
escaped removal during previous surgery and other
techniques have failed to localize the tumour(25).
Treatment of Pheochromocytoma
The optimal therapy for a pheochromocytoma is
prompt surgical removal after diagnosis in order to prevent
potentially lethal hypertensive crisis(6). Safe surgical removal
involves a team effort comprising of an internist, an
anesthesiologist and a surgeon with prior experience with
pheochromocytoma.
Preparation for surgery
The medical treatment is directed at controlling
hypertension (including hypertensive crisis during removal
of tumour, at maintaining stable blood pressure during
surgery and minimizing adverse effects of high
catecholamine levels during anesthesia). Maintain adequate
blood pressure control for two weeks prior to surgery.
Treatment should be initiated by use of a non competitive a
adrenoceptor blocker phenoxybenzamine (1mg/kg/d). Other
a –blocking drug with shorter duration of action are prazocin
(2-5 mg q 6 to 8 hrs), terazocin (2-5 mg OD) and doxazocin
(2-8 mg OD).
Labetalol(200-600mg q 12 hrs) has both a and b
antagonistic activity and can be given orally as well as
intravenously, but due to more of b antagonistic activity can
cause more slowing of heart rather than control of BP.
Once BP is controlled, the patient is given normal to high salt
diet to restore blood volume to normal and b blockers
(propanolol, esmolol) are only needed when significant
tachycardia or catecholamine induced arrhythmia occur.
These should never be given in absence of a blockade as that
might accelerate epinephrine induced vasoconstriction.
Metyrosine (1.5-4g/d) competitively inhibits tyrosine
hydroxylase which is the rate limiting step in catecholamine
biosynthesis. Calcium channel blockers have also been used
to control BP. Hypertensive crises is treated with short acting
agent like phentolamine (5 mg bolus or 100mg in 500 ml 5%
dextrose as intravenous infusion). Alternatively, continuous
infusion of sodium nitroprusside, nifedipine (10mg oral or
sublingual) can be used. The main goals in the operating
room are careful blood pressure monitoring, excellent
venous access, rapid and smooth induction of anaesthesia and
excellent exposure and minimal manipulation of the tumour.
To achieve these, arterial lines are placed in large vessels,
central venous line is put in, general anaesthesia induction is
done with inhaled anaesthetic agents, muscle relaxants
without hypertensive side effects (like vecuronium) used. A
Swan-Ganz catheter may be used in elderly and those with
cardiac dysfunction. Intraoperatively gentle handling of
tumour and dissecting patient from tumour is done to
prevent spillage and haemmorhage by tumour fracture(2).
Pheochromocytoma - revisited...................
Surgical Approach
Both operative techniques, laparoscopic (lateral
transabdominal approach and posterior retroperitoneal
approach) as well as open (transabdominal anterior approach,
lateral approach and posterior approach), are being used.
Laparoscopic approach with its multiple advantages like
reduced pain, smaller incision, more rapid recovery and
fewer complications is preferred in small (<3cm) to
medium(3-6cm) size tumours(26). For bilateral tumours
posterior retroperitoneal laparoscopic approach is considered
better over lateral transabdominal approach as the latter
requires the patient to be repositioned. In case the patient has
undergone previous abdominal operation posterior
retroperitoneal poses no problem whereas lateral
transabdominal approach may be difficult because of
adhesions. Posterior retroperitoneal approach offers no
abdominal explorations as compared to little exploration in
lateral approach(27).
Open approach was classically used particularly in the
case of familial pheochromocytoma. Open approach, as
compared to laparoscopic approach, allows access to both
adrenals and full explorations of intra abdominal,
retroperitoneal and extra adrenal deposits of tumour. This
approach is feasible for large tumour size (>6cm)(27,28). For
bilateral tumours open transabdominal anterior approach is
better than posterior approach but manipulation of tumour
by posterior approach may exceed that by anterior
approach(28). In cases of carcinomas open operations allows
best exposure as against laparoscopic approach(27,28). In case
the patient has under gone previous abdominal operations
open approach is more difficult than laparoscopic one.
(27,28) With growing expertise in advanced laparoscopic
procedures, recent reports show increasing trend towards
laparoscopic adrenalectomy in the past decade with special
stress on adrenal sparing surgery(29,30).
Post operative Management
In case hypotension develops during or after surgery,
volume replacement is the treatment of choice, dopamine
infusion may be required. The volume of fluid required is
often large during the first 24 – 48 hours due to decreased
sympathetic tone.
Postoperative hypertension during first 24 hours may be
done due to pain, volume overload or autonomic instability.
In case hypertension persists, essential hypertension is still
most likely diagnosis. Before discharge urine collection for
biochemical testing should be done. Repeat measurement
should be made if symptoms reappear or yearly for first 5 yrs
if patients remains asymptomatic. Operative mortality in
experienced hands is approximately 1.3 %(31). Long term
survival of benign pheochromocytoma is same as age
adjusted normal. Approximately 25% patients remain
hypertensive but easily controlled with medications(32).
Hereditary Pheochromocytoma
Upto 24% pheochromocytomas are inherited (in
KA Wani et al
autosomal dominant pattern)(5). Hereditary pheochromo-
cytoma is associated with multiple endocrine neoplasia type
2, von Reckling Hausen’s neurofibromatosis type 1, von
Hippel-Lindau (VHL) syndrome and succinate dehydro-
genase gene family(5,33).
Pathology
Sporadic pheochromocytomas are generally solitary,
well circumscribed, encapsulated tumours. These may still
be considered adrenal in origin if the cortex of the adrenal is
found in close relationship to the tumour. There is no
histopathological feature to distinguish malignant from
benign pheochromocytoma. Only the tumour invasion of
tissues and presence of metastatic lesions (most commonly in
liver, lungs, lymphatic nodes and bones) are consistent with
the diagnosis of malignancy(6,34). Most pheochromocytoma
range from 3 to 5 cm in size. Largest tumour reported was 20
cm in diameter(35).
Malignant Pheochromocytoma
Frequency of malignant pheochromocytoma ranges
from 13 to 34% with slight male predominance with half
occurring at presentation(36). The overall 5 yr survival rate
varies from 34% to 60%(37). Clinical manifestations of
malignant pheochromocytoma are similar to benign
counterpart. There is increased dopamine excretion and its
metabolites due to intraneuronal loss of dopamine b
hydroxylase as a consequence of cell dedifferentiation. Non
diploid DNA pattern is associated with an increased
likelihood of malignancy(38).
First line systematic therapy is targeted radiotherapy
using 131I-MIBG (50mCi to 900mCi), with this one third of
patients show partial response (50% reduction in tumour
mass) and improvement in symptoms(39). In rapidly
progressive metastatic tumour chemotherapy is
recommended using combination of cyclophosphamide
(750mg/m2) Vincristine (1.4 mg/m2) and dacarbazine 600
mg/m2)(CVD) administered I/V in 21 day cycles, with 57%
having complete or partial response. (40) External beam
radiotherapy is used in palliation of chronic pain and
symptoms of local compression(41).
Pheochromocytoma in Children
About 5 -10% of all pheochromocytoma occur in
children with an incidence of 2 per million, it is the most
common endocrine tumour in paediatric age group(42,43).
These are commonly familial (9-50%), extra adrenal (8-
43%), bilateral adrenal (7-53%) and multifocal with peak at
10 to 13 yrs of age. Less than 10% of paediatric pheochromo-
cytoma are malignant with a 5 yr survival of 40-50%(42).
In contrast to adults 70-90% of children present with
sustained hypertension. MRI is preferred over CT due to lack
of radiation exposure. MIBG can be used to localize tumour.
Treatment is similar to that in adults.
Pheochromocytoma in Pregnancy
Pheochromocytoma remains unrecognized antepartum
in 47% to 65% of patients and it carries a high morbidity and
27
IJEM 2007;11(3 & 4):23-29
mortality (40.3% maternal and 56% fetal)(44). Localization is
best done by MRI and /or ultrasonography(2). In case of
hypertensive crisis in pregnancy phentolamine (1-5 mg bolus
or 1 mg/min infusion) or sodium nitropruside (1 mg/kg/min)
can be use. In first two trimesters, the tumour should be
removed after adequate preoperative a-blockade while in
third trimester patient should be treated with a-blockers till
fetal maturity is reached followed by cesarean section. Labour
and vaginal delivery should be avoided(6,45).
CONCLUSION
Pheochromocytomas are rare, mostly benign
catecholamine-producing tumors of chromaffin cells of the
adrenal medulla or of a paraganglion. Typical clinical
manifestations are sustained or paroxysmal hypertension,
severe headaches, palpitations and sweating resulting from
hormone excess. However, their presentation is highly
variable and can mimic many other diseases. If remaining
unrecognized or untreated, they can be a life-threatening
condition. Therefore, the most important message of this
review is to think of them. Physicians commonly treating
hypertension should evaluate such patients for a possible
correctable cause. The diagnosis of pheochromocytomas
depends mainly upon the demonstration of catecholamine
excess by 24-h urinary catecholamines and metanephrines or
plasma metanephrines. They are localized by a computed
tomography scan and magnetic resonance imaging of the
adrenal glands and abdomen; complementary 123 I-
metaiodobenzylguanidine scintigraphy and 18F-
dihydroxyphenylalanine-positron emission tomography are
available. Because approximately one out of four
pheochromocytomas turn out to be hereditary entities,
screening for genetic alterations is important. Laparoscopic
and adrenal sparing surgical intervention following
preoperative alpha-blockade is the treatment of choice.
REFERENCES
1. Manger WM, Gifford RW. Pheochromocytoma. J Clin Hypertens
2002;4: 62-72.
2. Pacak K, Keiser H, Eisenhofer G. Pheochromocytoma. In DeGroot
LJ, Jameson JL, editors. Endocrinology 5th edition. Philadelphia,
Saunders, 2006, pp 2501-34.
3. Pacak K, Chrousos GP, Koch CA. Pheochromocytoma: Progress in
diagnosis, therapy, and genetics. In Margioris A, Chrousos GP,
editors. Adrenal Disorders, 1st edition. Totowa, Humana Press, 2001,
pp 479-523.
4. St. John Sutton MG, Sheps SG, Lie JT. Prevalence of clinically
unsuspected pheochromocytoma. Review of a 50-year autopsy series.
Mayo Clin Proc 1981;56: 354-359.
5. Mittendorf EA, Evans DB, Lee JE, Perrier ND. Pheochromocytoma:
Advances in genetics, diagnosis, localization, and treatment. Hematol
Oncol Clin North Am 2007;21(3): 509-25.
6. Manger W, Gifford R. Clinical and Experimental Pheochromo-
cytoma. Cambridge, MA: Blackwell Science 1996.
7. Bravo EL, Tagle R: Pheochromocytoma: State-of-the-art and future
prospects. Endocr Rev 2003;24: 539-53.
8. Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M,
Friberg P, et al. Biochemical diagnosis of pheochromocytoma: Which
28
test is best? JAMA 2002;287: 1427-34.
9. Gu Q, Shi X, Xu G. Advances in catecholamine analysis in biological
samples. Se Pu 2007;25(4): 457-62.
10. Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein
DS, Keiser HR. Plasma normetanephrine and metanephrine for
detecting pheochromocytoma in von-Hippel- Lindau disease and
multiple endocrine neoplasia type 2. N Engl J Med 1999;340: 1872-9.
11. Stenstrom G, Waldenstrom J. Positive correlation between urinary
excretion of catecholamine metabolites and tumour mass in
pheochromocytoma. Results in patients with sustained and
paroxysmal hypertension and multiple endocrine neoplasia. Acta
Med Scand 1985;217: 73-7.
12. Bravo EL, Tarazi RC, Fouad FM, Vidt DG, Gifford RW Jr. Clonidine-
suppression test: A useful aid in the diagnosis of pheochromocytoma.
N Engl J Med 1981;305: 623-6.
13. Levinson PD, Hamilton BP, Mersey JH, Kowarski AA. Plasma
norepinephrine and epinephrine responses to glucagon in patients
with suspected pheochromocytomas. Metabolism 1983;32: 998-
1001.
14. Maurea S, Cuocolo A, Reynolds JC, Neumann RD, Salvatore M.
Diagnostic imaging in patients with paragangliomas. Computed
tomography, magnetic resonance and MIBG scintigraphy
comparison. Q J Nucl Med 1996;40: 365-71.
15. Maurea S, Cuocolo A, Reynolds JC, Tumeh SS, Begley MG, Linehan
WM, et al. Iodine-131-metaiodobenzylguanidine scintigraphy in
preoperative and postoperative evaluation of paragangliomas:
Comparison with CT and MRI (see comments). J Nucl Med
1993;34: 173-9.
16. Mukherjee JJ, Peppercorn PD, Reznek RH, Patel V, Kaltsas G, Besser
M, et al. Pheochromocytoma: Effect of nonionic contrast medium in
CT on circulating catecholamine levels. Radiology 1997;202: 227-31.
17. Maurea S, Cuocolo A, Reynolds JC, Choyke PL, Keiser HR,
Neumann RD, et al. Role of magnetic resonance in the study of
benign and malignant pheochromocytomas: Quantitative analysis of
the intensity of the resonance signal. Radiol Med (Torino) 1993;85:
803-8.
18. Shapiro B, Sisson JC, Shulkin BL, Gross MD, Zempel S, et al. The
current status of radioiodinated metaiodobenzylguanidine therapy of
neuro-endocrine tumours. Q J Nucl Med 1995;39(4Suppl 1): 55-7.
19 Nakatani T, Hayama T, Uchida J, Nakamura K, Takemoto Y,
Sugimura K. Diagnostic localization of extra adrenal
pheochromocytoma: Comparison of I-MIBG imaging and I-
123 131
MIBG imaging. Oncol Rep 2002;9: 1225-7.
20. Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Li ST, Goldstein
DS. 6-[18F] fluorodopamine positron emission tomographic (PET)
scanning for diagnostic localization of pheochromocytoma.
Hypertension 2001;38: 6-8.
21. Ilias I, Yu J, Carrasquillo JA, Chen CC, Eisenhofer G, Whatley M, et
al. Superiority of 6-(18F)-fluorodopamine positron emission
tomography versus (131I)-metaiodobenzylguanidine scintigraphy in
the localization of metastatic pheochromocytoma. J Clin Endocrinol
Metab 2003;88: 4083-7.
22. Shulkin BL, Wieland DM, Schwaiger M, Thompson NW, Francis IR,
Haka MS, et al. PET scanning with hydroxyephedrine: An approach
to the localization of pheochromocytoma. J Nucl Med 1992;33:
1125-31.
23. Shulkin BL, Thompson NW, Shapiro B, Francis IR, Sisson JC:
Pheochromocytomas: Imaging with 2-(Fluorine-18) fluoro-2-
deoxy-D-glucose PET. Nucl Med 1999;212: 35-41.
24. Illias I, Pacak K. Current approaches and recommended algorithm for
the diagnostic localization of pheochromocytoma. J Clin Endocrinol
Metab 2004;89: 479-91.
25. Pacak K, Goldstein DS, Doppman JL, Shulkin BL, Udelsman R,
Eisenhofer G, et al. A “pheo” lurks: Novel approaches for locating
occult pheochromocytoma. J Clin Endocrinol Metab 2001;86: 3641-
6.
26. Thompson GB, Grant CS, van Heerden JA, Schlinkert RT, Young
WF Jr, Farley DR, et al. Laparoscopic versus open posterior
adrenalectomy: A case-control study of 100 patients. Surgery
Pheochromocytoma - revisited...................
1997;122: 1132-7.
27. Dixon MJ. Breast and Endocrine surgery. In Corson JD, Williamson
RCN (eds): Surgery. London, Mosby, 2001, pp 14.1-14.12.
28. Grant CS: Pheochromocytoma. In Clark OH, Duh QY, Kebebew E
(Eds): Textbook of Endocrine Surgery. Philadelphia, Saunders, 2005,
pp 621-33.
29. Plaggemars HJ, Targarona EM, van Couwelaar G, D Ambra M,
García A, Rebasa P, et al. What has changed in adrenalectomy? From
open surgery to laparoscopy? Cir Esp. 2005;77(3): 132-8.
30. Faria EF, Andreoni C, Krebs RK, Nascimento H, Goldman SM,
Kater C, et al. Advances in pheochromocytoma management in the
era of laparoscopy. J Endourol. 2007;21(11): 1303-7.
31. Sheps SG, Jiang NS, Klee GG, van Heerden JA. Recent developments
in the diagnosis and treatment of pheochromocytoma. Mayo Clin
Proc 1981;56: 88-95.
32. Young JB, Landsberg L. Catecholamines and adrenal medulla. In
Wilson JD, Foster DW (eds): Williams Textbook of Endocrinology.
Philadelphia, Saunders, 1998, pp 665-728.
33. Gimenez-Roqueplo AP, Lehnert H, Mannelli M, Neumann H,
Opocher G, Maher ER, Plouin PF. European Network for the Study
of Adrenal Tumours Pheochromocytoma Working Group.
Pheochromocytoma, new genes and screening strategies Clin
Endocrinol (Oxf). 2006;65(6): 699-705.
34. Yu J, Pacak K. Management of malignant Pheochromocytoma.
Endocrinologist 2002;12: 291-9.
35. Modlin IM, Farndon JR, Shepherd A, Johnston ID, Kennedy TL,
Montgomery DA, et al. Pheochromocytomas in 72 patients: Clinical
and diagnostic features, treatment and long term results. Br J Surg
1979;66: 456-65.
KA Wani et al
36. Glodny B, Winde G, Herwig R, Meier A, Kühle C, Cromme S, et al.
Clinical differences between benign and malignant pheochromo-
cytomas. Endocr J 2001;48: 151-9.
37. Mundschenk J, Lehnert H. Malignant pheochromocytoma. Exp Clin
Endocrinol Diabetes 1998;106: 373-6.
38. Nativ O, Grant CS, Sheps SG, O’Fallon JR, Farrow GM, van
Heerden JA, et al. The clinical significance of nuclear DNA ploidy
pattern in 184 patients with pheochromocytoma. Cancer 1992;69:
2683-7.
39. Rose B, Matthay KK, Price D, Huberty J, Klencke B, Norton JA, et al.
High dose 131I-metaiodobenzylguanidine therapy for 12 patients
with malignant pheochromocytoma. Cancer 2003;98: 239-48.
40. Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS,
Stull R, et al. Malignant pheochromocytoma: Effective treatment
with a combination of cyclophosphamide, vincristine, and
decarbazine. Ann Intern Med 1988; 109:267-73.
41. Yu L, Fleckman AM, Chadha M, Sacks E, Levetan C, Vikram B.
Radiation therapy of metastatic pheochromocytoma: Case report and
review of literature. Am J Clin Oncol 1996;19: 389-93.
42. Reddy VS, O’Neill JA Jr, Holcomb GW 3rd, Neblett WW 3rd, Pietsch
JB, Morgan WM 3rd, et al. Twenty five year surgical experience with
pheochromocytoma in children. Am Surg 2000;66: 1085-
91(discussion 1092).
43. Ludwig AD, Feig DI, Brandt ML, Hicks MJ, Fitch ME, Cass DL.
Recent advances in the diagnosis and treatment of
pheochromocytoma in children. Am J Surg. 2007;194(6): 792-6;
discussion 796-7.
44. Oishi S, Sato T. Pheochromocytoma in pregnancy. A review of the
Japanese literature. Endocr J 1994;41 :219-25.
45. Manger WM Jr. Pheochromocytoma. New York, Springer- Verlag,
1977.
29
UPDATE ARTICLE

Role of Adiponectin in disease

Mohammad Hayat Bhat, Manzoor Ahmad
Department of Medicine, Govt. Medical College Associated S.M.H.S. Hospital, Srinagar, Kashmir

ABSTRACT

Obesity and obesity related disorders play an important role in clinical medicine. Adipose tissue is an active
metabolic tissue that secretes multiple metabolically active soluble mediators called as adipokines. Adiponectin,
a prototypical adipokine is important because of its beneficial effects on glucose and lipid metabolism.
Adiponectin levels are decreased in obesity and disease states such as diabetes and cardiovascular diseases. Direct
administration of adiponectin has been shown to be beneficial in animal models of obesity, diabetes and
atherosclerosis. This article will survey the physiological functions and therapeutic options available with
adiponectin. [IJEM 2007;(3&4):31-34]
Key words: adiponectin, insulin resistance, obesity, thiazolidinedione, type 2 diabetes mellitus.

INTRODUCTION collagen super family, sharing significant homology with

Adipose tissue is an important endocrine organ
secreting multiple metabolically active proteins termed
adipokines. Some well known adipokines including
leptin(1), tumor necrosis factor (TNF)-a (2), plasminogen
activated inhibited (PAI)–1 (3), adipsin(4), resistin(5),
interleukin (IL) - 6 and adiponectin.
Newly discovered adipokines include visfatin(6) and
retinol binding protein – 4 (RBP 4), which was found to be
up regulated in adipose tissue of adipose specific GLUT 4
knockout mice(7).
Adiponectin is a novel collagen like protein synthesized
by white adipose tissue that circulates at relatively high (2 – 20
µg/ ml) serum concentration. It has gained importance for its
role in glucose and lipid metabolism(8). Multiple studies
have shown a strong positive relationship between
adiponectin and insulin sensitivity(9-13). More recent
studies have shown a role for adiponectin in cardiovascular
disease(14,15).
Chemical Structure
Adiponectin structurally belongs to the soluble defense
Address for Correspondence
Dr. Mohammad Hayat Bhat,
Endocrinologist Department of Medicine, Govt. Medical College
Associated S.M.H.S. Hospital, Srinagar, Kashmir-190010, INDIA
E-mail: hayatmb@rediffmail.com; Mob.: 0941908170
Fax 01942479523.
collagen X, collagen VIII and compliment factor C1Q. The
basic structure is a 247 amino acid protein with four domains.
A hyper variable amino terminal, a variable region followed
by a collagenous domain and a carboxy terminal globular
domain(16) (Figure 1).
COOH
H2N Variable Region Collagenous Domain Globular Domain
Figure 1: Structure of Adiponectin
Adiponectin undergoes post translational modification
during its secretion from adipocytes. Several lysine and
proline residues within the collagenous domain are
hydroxylated. Hydroxyl lysine residues at position 68, 71, 80
and 104 are further modified by a glucosyl a (1 – 2 galactosyl
group).
Oligomerization of Adiponectin
Monomeric forms of Adiponectin undergo
transformation into multiple forms including trimers,
hexamers and high molecular weight (HMW) oligomers(16-
19) (Figure 2). These forms range in size from 7 – 90 kDa
trimers to approximately 500 kDa high molecular weight
forms.
The relative distribution of adiponectin among these

31
IJEM 2007;11(3 & 4):31-34
Monomer Trimer Hexamer HMW
Figure 2: Oligomerization of Adiponectin
multimeric forms differs between the adipose tissue and the
circulation with high molecular weight forms dominating in
plasma(19,20).
Scherer et al defined a new index, SA, as the ratio of
HMW form to the total Adiponectin is equal to HMW/
(HMW + LMW) where the total Adiponectin equals the sum
of high (HMW) and low (LMW) molecular weight forms.
They showed that SA had a stronger correlation with insulin
sensitivity than total adiponectin levels at both baseline and
after thiazolidinedione treatment(16).
Several single nucleotide polymorphisms (SNP) of the
Adiponectin gene have been identified, SNP 45 and SNP 276
being the most common. In the Japanese population, SNP
276 was associated with lower plasma Adiponectin levels and
higher insulin resistance and increase risk for type 2 diabetes.
Mechanism of action
One potential mechanism of Adiponectin has been
suggested by identification of two transmembrane receptors.
Adipo R1, which is predominantly expressed in the skeletal
muscles, shows a preference for globular Adiponectin (gAd),
whereas Adipo R 2 which is predominantly expressed in liver
shows a preference for full length Adiponectin(21).
Kadowaki’s group has shown that Adiponectin acts through
activation of AMP kinase and PPARa in both liver and
skeletal muscles, which results in stimulation of fatty acid
oxidation and decreased triglyceride content in skeletal
muscle and liver(22).
Physiological role
Over past several years, the functions of Adiponectin
have been extensively studied in numerous animal models
and invitro systems. It is now appreciated that Adiponectin is
a multifunctional protein that regulates insulin sensitivity,
energy homeostasis, vascular reactivity, inflammation, cell
proliferation and tissue remodeling. Thus far identified
targets of adiponectin include liver, skeletal muscle, adipose
tissue, brain, pancreas, macrophages and blood vessels
(Figure 3).
Epidemiology
Low levels of adiponectin are associated with adverse
metabolic states such as diabetes, metabolic syndrome,
dyslipidemia, lipodystrophy, and atherosclerotic
cardiovascular disease(23,24,25). Both gender and ethnicity
also effect adiponectin levels. Adiponectin levels are generally
lower in men compared with women. Women also have
higher content of the HMW forms adiponectin. Higher
plasma levels of adiponectin are found in Caucasians
32
Cytokine induced Energy Expenditure Proliferation
Apoptosis Glucose uptake Body Weight Migration
Pancreatic â cell Adipocyte Brain Smooth Muscles
Gluconeogenesis
Steatosis Vasodilation
Liver ADIPONECTIN Endothelial Adhesion
Inflamation
Fibrosis
Skeletal Muscles Heart Macrophages
Fatty Acid Oxidisation
Insulin Sensitivity Ischemic Injury Foam Cell Formation
compared with body mass index [BMI]-matched Indo-
Asians and Blacks.
In contrast to other adipokines which increase as the fat
mass increases, circulation levels of adiponectin are
paradoxically decreased in obese subject compared with lean
subjects. On the other hand weight reduction by gastric
partition surgery or calorie reduction leads to an increase in
plasma level of adiponectin. There is a strong inverse
correlation between plasma level of adiponectin and measure
of adiposity; including BMI and total fat mass. Furthermore
hypoadiponectinemia has been found to be closely associated
with both congenital and HIV related lipodystrophy, a disease
characterized by body fat redistribution
Adiponectin and Insulin sensitivity
Multiple animal and human studies have shown a
correlation between plasma adiponectin levels and insulin
sensitivity. Decline in plasma levels of adiponectin seems to
identify insulin resistance before development of overt
diabetes. Low plasma levels of adiponectin are observed in
severe forms of diabetes and insulin resistance like type 2
diabetes, gestational diabetes, diabetes associated with
lipodystrophy(26,27,28).
Adiponectin and Cardiovascular Diseases
Adiponectin is inversely correlated with traditional
cardiovascular risk factor including blood pressure, heart
rate, low-density lipoproteins (LDL), cholesterol and
triglycerides levels and positively related to high density
lipoprotein (HDL), cholesterol level. Hypo adiponecti-
nemiaema has been found to be independent risk factor for
endothelial dysfunction, and regardless of insulin
resistance(11). In addition, the association of low levels of
adiponectin with coronary artery disease and Ischemic
cerebrovascular disease was also reported to be independent
of classical cardiovascular risk factors such as diabetes,
dyslipidemia and hypertension.
Adiponectin and chronic liver disease
Many recent studies demonstrated a close association of
low adiponectin levels with non alcoholic fatty liver disease
Adiponectin in health .......................
(NAFLD) and non-alcoholic steatohepatosis (NASH)(29).
In contrast to NAFLD and NASH, plasma levels of
adiponectin are significantly elevated in patients with liver
disease. Adiponectin was reported to alleviate alcoholic and
nonalcoholic fatty liver disease and liver fibrosis in mice.
Further studies will be needed to determine the physiological
and pathophysiological roles of Adipo R1 and Adipo R2 in
these .
Adiponectin and Cancers
A strong inverse association between plasma
adiponectin levels and risk of both breast cancer and
endometrial cancer has recently been reported. Plasma
adiponectin levels in patients with gastric cancer were
reported to be much lower than in control subject. Hypo
adiponectinemia was found to be an independent predictor
for future development of colorectal cancer. Recently,
adiponectin was reported to induce antiangiogenesis and
antitumour activity via caspace mediated endothelial cell
apoptosis(30).
Therapeutic effects of Adiponectin
Administration of adiponectin has been shown to
improve insulin sensitivity in mouse models of diabetes and
lipoatrophy.In both wild type mice and mouse models of type
1 and type 2 diabetes intraperitoneal injection of full length
adiponectin resulted in a significant reduction of glucose
levels. Similar results were shown by Yamauchi et al using
systemic infusion of the globular domain of adiponectin in
mouse models of obesity, diabetes and lipoatrophy, full length
forms of adiponectin was without effect(31). Yamauchi et al
showed that transgenic mice over expressing gAd
demonstrated protection from high-fat-fed-induced insulin
resistance. Yamauchi et al demonstrated in a mouse model for
atherosclerosis (apolipoprotein E deficient) that gAd can
protect against atherosclerosis(32). Ouchi et al showed that
adiponectin suppressed macrophage-to- foam cell
transformation in vitro .They also demonstrated the effects
of adiponectin to suppress monocyte adhesion to
endothelium, myeloid differentiation and macrophage
cytokine production and phagocytosis, all important steps in
the development of vascular disease(33-34).
Adiponectin Up regulation as a Therapeutic Option
Results obtained from animal experiments and human
epidemiological studies support the role of adiponectin as a
potential target for developing novel therapeutic agents
against obesity related disease. However this would be
difficult to achieve in clinical setting, owing to the large
protein structure of adiponectin and the need for post
translational modification . Thus therapeutic possibilities
have focused on the upregulation of adiponectin through
indirect methods such as thiazolinedione therapy or weight
loss.
It has been shown that thiazolinedione treatment
results in elevated circulating levels of adiponectin in mice
and humans(35). These effects seem to be associated with
Bhat M Hayat et al
small-sized adipocytes, adipocytes differentiation with
increased synthesis and/or secretion of Adiponectin. Besides
direct transcriptional activation of genes via peroxisome
proliferator response element and increased insulin action.
Interestingly, both PPARg agonists and adiponectin have
been shown to increase insulin sensitivity and ameliorate
atherosclerosis(36). Rimonabant a selective cannabinoid
(CB1) receptor antagonist acts on the adipocyte CB1
receptors and increases secretion of adiponectin.
Weight loss is another strategy for increasing
adiponectin levels .Several studies have demonstrated an
increase in adiponectin levels after significant weight loss
induced by gastric bypass surgery. Significant weight loss
mean 14% reduction in BMI through intensive life style
changes can result in increase in adiponectin levels. The
other strategy may be to up-regulate adiponectin receptors or
to stimulate adiponectin receptors using small molecule
agonists.
CONCLUSION
It is now known that adipose tissue is a dynamic
endocrine organ secreting multiple adipokines. Adiponectin
is an important adipokine that is secreted only by adipose
tissue and circulates at highly abundant levels. Adiponectin
has an important role in carbohydrate and lipid metabolism as
seen in the association of low levels of adiponectin with
disease state such as insulin resistance, type 2 diabetes and
cardiovascular diseases.
Though administration of Adiponectin has shown
benefits in improving insulin resistance and atherosclerosis
in animal models, human trials have not been possible.
Indirect methods for raising adiponectin levels include
thiazolidinedine therapy and weight loss. Thiazo-
lidinedones have a significant effect on adiponectin levels and
may have an added advantage of increasing the HMW forms
In addition to these effects; adiponectin also seems to have
pleiotropic effects, particularly in relation to metabolic
syndrome.
REFERENCES
1. Friedman JM. Obesity in the new millennium. Nature 2000;404:
632–634.
2. Hotamisligil GS. The role of TNFa and TNF receptors in obesity
and insulin resistance. J Intern Med 1999;245: 621–625.
3. Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K,
Nakamura T, et al. Enhanced expression of PAI-1 in visceral fat:
possible contributor to vascular disease in obesity. Nat Med 1996;2:
800–803.
4. White RT, Damm D, Hancock N, Rosen BS, Lowell BB, Usher P, et
al. Human adipsin is identical to complement factor D and is
expressed at high levels in adipose tissue. J Biol Chem 1992;267:
9210–9213.
5. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM,
et al. The hormone resistin links obesity to diabetes. Nature 2001;409:
307–312.
6. Fukuhara A, Matsuda M, Nishizawa M et al. Visafatin: a protein
secreted by visceral fat that mimics the effect of insulin. Science
2005;307(5708): 426-430.
33
IJEM 2007;11(3 & 4):31-34
7. Yang Q, Graham TE, Mody N et al. Serum retinol binding protein 4
contributes to insulin resistance in obesity and diabetes.Nature
2005;436(7049): 356-362.
8. Chandran M, Phillips SA, Ciaraldi T, Henry RR Adiponectin; more
than just another fat cell hormone? Diabetes Care 2003;26(8): 2442-
2450.
9. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The
adipocyte-secreted protein Acrp30 enhances hepatic insulin action.
Nat Med 2001;7: 947-953.
10. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous
glucose production is inhibited by the adipose-derived protein
Acrp30. J Clin Invest 2001;108: 1875-1881.
11. Hotta K, Funahashi T, Bodkin NL et al. Circulating concentrations of
the Adipocyte protein adiponectin are decreased parallel with
reduced insulin sensitivity During the progression to type 2 diabetes
in rhesus monkeys. Diabetes 2001;50(5): 1126-1133.
12. Staffes MW, Cross MD, Schreiner PJYuX , Hilner JE ,Gingerich R et
al. Serum adiponectin in young adults Interaction with central
adiposity, circulating levels of glucose, and insulin resistance: the
CARDIA study. Ann Epidemol 2004;14(7): 492-498.
13. Weyer C, Funahashi T, Tanaka S et al. Hypoadiponectinemia in
obesity and type 2 diabetes; close association with insulin resistance
and hyperinsulinemia. J Clin Endocrinol Metab 2001;86(5): 1030-
1035.
14. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y,
et al. Plasma concentrations of a novel, adipose-specific protein,
adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc
Biol 2000;20: 1595–1599.
15. Pishon T, Girman CJ, Hotamisligil CS, Rifai N, Hu FB, Rimm EB.
Plasma adiponectin levels and risk of myocardial infarction in men.
JAMA 2004;291(14) :1730-1737.
16. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel
serum protein similar to C1q, produced exclusively in adipocytes. J
Biol Chem 1995;270: 26746-26749.
17. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, et al.
Paradoxical decrease of an adipose-specific protein, adiponectin, in
obesity. Biochem Biophys Res Commun 1999;257: 79-83.
18. Tsao T-S, Murrey HE, Hug C, Lee DH, Lodish HF. Oligomerization
state-dependent activation of NF-kB signaling pathway by adipocyte
complement-related protein of 30 kDa(Acrp30). J Biol Chem
2002;277: 29359–29362.
19. Waki H, Yamauchi T, Kamon J, Kita S, Ito Y, Hada Y, et al. Generation
of globular fragment of adiponectin by leukocyte elastase secreted by
monocytic cell line THP-1. Endocrinology 2005;146: 790–796.
20. Phillips SA, Ciaraldi TP, Kong AP, et al. Modulation of circulating
andadipose tissue adiponectin levels by antidiabetic therapy.Diabetes
2003;52(3): 667-674.
21. Yamauchi T, Hara K, Kubota N, Terauchi Y, Tobe K, Froguel P, et al.
Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-
atherogenic adipokine. Curr Drug Targets Immune Endocr Metabol
Disord 2003;3: 243–254.
22. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, et al.
Adiponectin stimulates glucose utilization and fatty-acid oxidation by
activating AMP-activated protein kinase. Nat Med 2002;8:
1288–1295.
34
23. Mohan V, Deepe R, Pradeepa R, et al. Association of low adiponectin
levels with the metabolic syndrome - the Chennai Urban Rural
epidemiological study (CURES-4). Metabolism 2005;54(4): 476-
481.
24. Shetty GK, Economides PA, Horton ES, Mantzoros CS, Veves A.
Circulating adiponectin and resistin levels in relation to metabolic
factors, inflammatory markers, and vascular reactivity in diabetic
patients and subjects at risk for diabetes. Diabetes Care 2004;27(10):
2450-2457.
25. Chen D, Misra A, Garg A. Clinical review 153; lipodystrophy in
human immuno deficiency virus infected patients. J Clin Endocrinol
Metab 2002;87(11): 4845-4856.
26. Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S,
Tataranni PA, et al. Adiponectin and development of type 2 diabetes in
the Pima Indian population. Lancet 2002;360: 57–58.
27. Retnakaran R, Hanley AJ, Raif N, Connelly PW, Sermer M, Zinman
B. Reduced adiponectin concentration in women with gestational
diabetes: a potential factor in progression to type 2 diabetes
2004;27(3): 799-800.
28. Williams MA, Qiu C, Muy-Rivera M, Vadachkoria S, Song T, Luthy
DA. Plasma adiponectin concentrations in early pregnancy and
subsequent risk of gestational diabetes mellitus. J Clin Endocrinol
Metab 2004;89(5): 2306-2311.
29. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-
derived hormone adiponectin alleviates alcoholic and nonalcoholic
fatty liver diseases in mice. J Clin Invest 2003;112: 91-100.
30. Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y,
Zhivotovsky B, et al. Adiponectin-induced antiangiogenesis and
antitumor activity involve caspase-mediated endothelial cell
apoptosis. Proc Natl Acad Sci USA 2004;101: 2476-2481.
31. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al.
The fat-derived hormone adiponectin reverses insulin resistance
associated with both lipoatrophy and obesity. Nat Med 2001;7: 941-
946.
32. Yamauchi T, Kamon J, Waki H, Imai Y, Shimozawa N, Hioki K, et al.
Globular adiponectin protected ob/ob mice from diabetes and apoE-
deficient mice from atherosclerosis. J Biol Chem 2003;l278: 2461-
2468.
33. Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, et
al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid
accumulation and class A scavenger receptor expression in human
monocyte-derived macrophages. Circulation 2001;103: 1057-1063.
34. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, et al.
Novel modulator for endothelial adhesion molecules: adipocyte-
derived plasma protein adiponectin. Circulation 1999;100:
2473–2476.
35. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida
K, et al. PPAR ligands increase expression and plasma concentrations
of adiponectin, an adipose-derived protein. Diabetes 2001;50: 2094-
2099.
36. Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, Matsubara
K, et al. Effects of pioglitazone on metabolic parameters, body fat
distribution, and serum adiponectin levels in Japanese male patients
with type 2 diabetes. Metabolism 2002;51: 314-317.
CASE REPORT

Management of macroprolactinomas in Pregnancy-

Report of two cases

Kulshreshtha B*, Jyotsna VP*, Kriplani A**, Kumar Sonesh**, Seith A***, Ammini AC*.
Departments of *Endocrinology and Metabolism, **Gynecology and Obstetrics and ***Radiology,All India Institute of Medical Sciences, New
Delhi, India

ABSTRACT
Management of a pregnant patient with prolactinoma is complex. The propensity for tumor growth under estrogenic
stimulation of pregnancy and effects of therapy on fetal development are major concerns. Monitoring of these patients with
regular prolactin assays is difficult due to elevations of prolactin seen during normal pregnancy and lactation. Many studies
have reported a 20-30% risk of tumor progression during pregnancies in patients with macroprolactinoma. Based on these
studies, regular field testing / imaging in these patients is advocated. Imaging studies are expensive and unpractical in Indian
context. We report course of two successful pregnancies in patients with macroprolactinomas. Monitoring of these patients
with prolactin levels and timely institution of bromocriptine therapy may be sufficient for managing pregnancy in these
patients. Pituitary apoplexy could occur even when prolactin levels are maintained in the normal (for pregnancy) range with
bromocriptine. [IJEM 2007;(3&4):35-37]
Key words- Macroprolactinoma, pregnancy, lactation, apoplexy, cabergolin, galactorrhea

INTRODUCTION Cabergoline initiation resulted in resumption of normal

Management of a pregnant patient with prolactinoma is
complex. The propensity for tumor growth under estrogenic
stimulation of pregnancy and effects of therapy on fetal
development are major concerns. Also, monitoring of these
patients with regular prolactin assays is difficult due to
elevations of prolactin seen during normal pregnancy and
lactation. Many studies have reported a 20-30% risk of tumor
progression during pregnancies in patients with
macroprolactinoma(1,2,3,4,5). Based on these studies,
regular field testing / imaging in these patients is advocated.
Imaging studies are expensive and unpractical in Indian
context. We report course of two successful pregnancies in
patients with macroprolactinomas.
Case 1
periods and a positive pregnancy test four months later.
Therapy was stopped and patient was advised to follow up
with monthly prolactin monitoring. Table 1 gives the
prolactin levels throughout pregnancy and lactation.
Bromocriptine was initiated only when prolactin levels rose
to above 250ng/ml. Bromocriptine was stopped postdelivery,
MRI done fourth month postpartum did not reveal any
appreciable change in size of the pituitary tumor. She has
been restarted on bromocriptine therapy.
Table 1: Prolactin levels of patients 1 and 2 during pregnancy
PATIENT 1
Month of gestation Prolactin levels (ng/ml) Intervention

This patient age 23 years, married for two years First 35.2 -
presented with complaints of galactorrhoea, irregular periods Second 81.3 -
and infertility. Investigations revealed high prolactin Third 135.4 -
levels(186.7ng/ml) and pituitary macroadenoma. Fifth 302 Bromocriptine 2.5 mg
Sixth 208 -
Address for Correspondence: Seventh 224 -
Jyotsna VP, Assistant Professor,Department of Endocrinology and Eighth 307 -
Metabolism, All India Institute of Medical Sciences, Delhi, India. Ninth Delivered -
E mail- vivekapjyotsna@yahoo.com First month lactation 145.6 -

35
IJEM 2007;11(3 & 4):35-37

PATIENT2 Visual field charting was normal. Prolactin levels rose to 326
ng/ml next month when she was initiated on bromocriptine
Month of gestation Prolactin levels (ng/ml) Intervention
2.5 mg/day. She was admitted to Gynecology in the second
Second 0.5 - trimester (sixth month) with complaints of fever and
Fourth 23 - headache. Prolactin levels were 160 ng/ml. MRI sella
Fifth 326 Bromocriptine 2.5 revealed intratumoral bleed. She was treated conservatively
Sixth 160 - with intravenous fluids, head ache and fever improved. She
Seventh 95 - delivered at 33 weeks, birth weight of the child was-2.28 kg.
Ninth 124 -
Normal lactation was established, post delivery MRI showed
First month lactation 252 -
no change in the size of the tumor.

Case 2
A 22 year old lady, married for two years presented with
a history of secondary amenorrhoea and galactorrhoea for 10
months. Investigations revealed primary hypothyroidism
and hyperprolactinemia (T4 - 0.54 (0.89-1.76 ng/dl), TSH -
42.7 mU/L (0.3 - 4 mU/L), serum prolactin - 472 ng/ml (6-
29ng/ml). Hyperprolactinemia persisted even after attaining
a euthyroid status. MRI sella revealed pituitary
macroadenoma. The visual field charting was normal. A
Figure 1: MRI of patient 2 showing intratumoral bleed
diagnosis of macroprolactinoma with primary hypo-
thyroidism was made. She was prescribed Tab Cabgoline 0.5
mg twice a week and 50 micrograms of thyroxin daily.
Contraception was advised. Patient had single menstrual
period after one month of starting therapy followed by
amenorrhoea next month. Preg colour test was found
positive. Hormonal profile was (PRL < 0.5 ng/ml,T4= 8
(5.1 – 14 microg/dl) and TSH = 3.48 mU/L). Cabgoline was
stopped and she was advised to continue on thyroxine 50
micrograms/day and she was advised to follow up with
prolactin levels. 6 weeks later, she had severe headache from
temples to occiput with altered consciousness. She was taken
to a local hospital where she was given intravenous fluids.
This headache subsided over two days. She was
normotensive at this visit, prolactin levels were 23 ng/ml.
DISCUSSION
Prolactinomas are common pituitary tumors usually
presenting as infertility in women. The impaired
reproductive endocrine axis in these patients is mostly
reversible with therapy. However, enlargement of tumor due
to stimulatory effect of estrogens on lactotrophs is a major
concern. A recent meta analysis has reported a 2.6% risk of
symptomatic increase in size in microprolactinomas during
pregnancy(6). In comparison, the risk of tumor progression
during pregnancies for patients with macroprolactinoma is
much higher, around 31%(1,2,3,4). Therefore, we advise
contraception during treatment in patients with
macroprolactinoma. Some patients, however, do not follow
this advice and present with conception a few months after
initiation of therapy.
Prolactin rises linearly throughout normal pregnancy
reaching concentrations of 150 –200 ng/ml at term(7). Levels
of prolactin reach as high as 60-70ng/ml during the first
trimester, increasing to 100 ng/ml during the second
trimester and peaking to 140-180 ng/ml during the third
trimester(7,8,9). Prolactin levels remain high till upto six
months postpartum with levels as high as 150 ng/ml in the
first month of lactation. Based on the natural progression
history of macroprolactinomas, it is generally agreed that
routine visual field testing/imaging be undertaken in a patient
with macroprolactinoma. In the Indian context however,
routine repeated imaging is unpractical.
Given the tranplacental transfer of all the dopaminergic
agents, stopping of medical therapy is recommended during
pregnancy in patients with prolactinoma. In case of
symptomatic enlargement, however, use of bromocriptine
therapy is advocated with a greater experience and least
incidence of side effects compared to other formulations.
Cabergoline has also been found to be safe, but due to its use
in a limited number of patients, its use is restricted to patients
intolerant to bromocriptine. Data in about 350 cases of use of
cabergoline during pregnancy has shown no increased risk of
adverse effects on fetus such as spontaneous abortions,
congenital malformations, multiple pregnancies or
prematurity(10,11,12).
Our first patient was managed conservatively with
monitoring of monthly prolactin levels. Bromocriptine was
instituted only when serum prolactin levels rose to more than

36
Management of macroprolactinomas in pregnancy............
250 ng/ml, levels more than in a normal pregnancy. MRI
done postpregnancy did not reveal any appreciable change. In
comparison, the second patient had a more dramatic course
with pituitary apoplexy necessitating hospital admission.
Pituitary apoplexy is a known complication related to the
hypervascularity of pituitary gland during pregnancy.
Lactation was successfully established in both patients.
In conclusion, it is possible to maintain prolactin in the
normal range (for pregnancy) with bromocriptine therapy.
Monitoring of these patients with prolactin levels and timely
institution of bromocriptine therapy may be sufficient for
managing pregnancy in these patients. Pituitary apoplexy
could occur even when prolactin levels are maintained in the
normal (for pregnancy) range with bromocriptine.
REFERENCES
1. Gemzell C, Wang CF. Outcome of pregnancy in women with
pituitary adenoma. Fertil Steril 1979;31: 363–372.
2. Kupersmith MJ, Rosenberg C, Kleinberg D. Visual loss in pregnant
women with pituitary adenomas. Ann Intern Med 1994;121: 473-
477.
3. Molitch ME. Pregnancy and the hyperprolactinemic woman. N Engl
J Med 1985;312: 1364-1370.
4. Musolino NR, Bronstein MD. Prolactinomas and pregnancy. In:
Bronstein MD, ed. Pituitary tumors and pregnancy. Norwell, MA:
Kluwer Academic Publishers 2001;91-108.
Kulshreshtha B et al
5. Webster J, Piscitelli G, Polli A, Ferrari CI, Ismail I, Scanlon MF. A
comparison of cabergoline and bromocriptine in the treatment of
hyperprolactinemic amenorrhea. Cabergoline Comparative Study
Group. N Engl J Med 1994;331: 904-909.
6. Gillam MP, Molitch ME, Lombardi G, Colao A. Advances in the
treatment of prolactinomas. Endocr Rev. 2006;27(5): 485-534.
7. L.A. Rigg, A. Lein, S.S.C. Yen. Pattern of increase in circulating
prolactin levels during human gestation Current Investigation
1977;129(4): 454-456.
8. Yin P, Arita J. Differential regulation of prolactin release and
lactotrope proliferation during pregnancy, lactation and the estrous
cycle. Neuroendocrinology 2000;72: 72–79.
9. Ferriani RA, Silva-de-Sa MF, de-Lima-Filho EC. A comparative
study of longitudinal and cross-sectional changes in plasma levels of
prolactin and estriol during normal pregnancy. Braz J Med Biol Res
1986;19: 183-188.
10. Ricci E, Parazzini F, Motta T, Ferrari CI, Colao A, Clavenna A, Rocchi
F, Gangi E, Paracchi S, Gasperi M, Lavezzari M, Nicolosi AE, Ferrero
S, Landi ML, Beck-Peccoz P, Bonati M. Pregnancy outcome after
cabergoline treatment in early weeks of gestation. Reprod Toxicol
2002;16: 791-793.
11. Robert E, Musatti L, Piscitelli G, Ferrari CI. Pregnancy outcome after
treatment with the ergot derivative, cabergoline. Reprod Toxicol
1996;10: 333-337.
12. Ciccarelli E, Grottoli S, Razzore P, Gaia D, Bertagna A, Cirillo S,
Cammarota T, Camanni M, Camanni F. Long-term treatment with
cabergoline, a new long-lasting ergoline derivate, in idiopathic or
tumorous hyperprolactinaemia and outcome of drug-induced
pregnancy. J Endocrinol Invest 1997;20: 547-551.
37
CASE REPORT

Exaggerated Thelarche - an uncommon presentation of sexual

maturation
Ashiq Masood, Ibrahim Masoodi, Abdul Rashid Shah, Sobia Nisar*, Junaid Yaseen, M Ashraf Ganie
Department of Endocrinology and Metabolism, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India

ABSTRACT

Isolated premature thelarche commonly affects the girls between 2-6 years (90% <2years). Majority of cases are self limited
and are not accompanied by advancement in height or bone age or premature menarche. Since the condition can represent
the initial manifestation of a slowly progressive variant of true central precocious puberty, the differentiation of these
conditions is important. We present girl who presented with a rare combination of thelarche with advanced bone and skeletal
age, without any elevation of sex steroids, and had no other features of the true precocious puberty. The girl on 3½ years
follow-up had normal growth pattern and no further progression in the sexual maturation. [IJEM 2007;(3&4):39-40]
Key words: Thelarche, sexual precocity, LHRH stimulation, sexual maturation.

INTRODUCTION full term uneventful forceps assisted delivery with normal

Isolated premature thelarche commonly affects the
girls between 2-6 years (90% <2years). Majority of cases are
self limited and are not accompanied by advancement in
height or bone age or premature menarche(1). Since the
condition can represent the initial manifestation of a slowly
progressive variant of true central precocious puberty, the
differentiation of these conditions is important. Stanhope
and Brook enountered cases of sexual maturation whose
LHRH responses were intermediate between the above two
conditions(2). Subsequently Garibaldi et al demonstrated
estrogen production in response to GnRHa challenge was
increased (commensurate with tissue effects like advanced
bone age, height age and firm breast consistency) as
compared to isolated thelarche but was lower (50%) than the
levels in true precocious puberty(3). We present girl who
presented with a rare combination of thelarche with
advanced bone and skeletal age, without any elevation of sex
steroids, and had no other features of the true precocious
puberty. The girl on 3½ years follow-up had normal growth
pattern and no further progression in the sexual maturation.
Case Report
K.B. a 6 year female child, first in birth order, born of
Address for correspondence
Dr. Mohd Ashraf Ganie, Assistant Professor,
Department of Endocrinology and Metabolism, Sheri-Kashmir
Institute of Medical Sciences, Srinagar, J& K, India-190014. Ph: 91-
194-2435712, M: 91-9419041546, Fax: 91-194-2403470,
E-mail:ashraf.endo @gmail.com
mental and motor development was brought to our clinic
with complaints of precocious breast development of one
year. Child also had gained a weight of 8 Kgs over a period of
four months. Parents gave no history of vaginal bleeding,
appearance of any pubic or axillary hair, constipation, cold
intolerance, features suggestive of hypothyroidism or any
drug intake. Clinical examination revealed an active child,
weighing 26 Kgs (>95th percentile by ICMR growth chart),
with a height of 118 cms (>95th percentile with target height
of 154 cms falling in 75th percentile by ICMR growth chart
4), upper segment /lower segment ratio of 0.98, head
circumference of 50 cms and an arm span of 115 cms. Breasts
were Tanner stage III. Height age was advanced height (~9.5
years) and corresponding bone ages (10.6 years by TW2
method). Rest of the clinical examination was unremarkable.
Investigations revealed normal blood counts, urinalysis,
electrocardiography, chest roentgenography, liver and kidney
functions. USG abdomen showed uterus measuring 37x11
mm with a faint endometrial lining and normal adrenal and
ovarian anatomy. Contrast enhanced CT scan abdomen
showed no adrenal or ovarian lesion. MRI brain especially of
hypothalamus and pituitary region showed normal anatomy.
Hormonal evaluation showed normal thyroid functions,
estradiol, basal androgens, and gonadotrophins (Table 1a).
ACTH stimulation test was not suggestive of any adrenal
steroidogenesis enzyme defects (Table 1b). LHRH
stimulation test using 100 µg of Triptorelin revealed a
prepubertal response (Table 1c).

39
IJEM 2007;11(3 & 4):39-40

Table 1a: Basal hormonal profile of the patient. responses were intermediate between the above two
Hormone Value Normal range (units ) conditions(1). Subsequently Garibaldi et al demonstrated
FT3 4.05 2.3-4.20 µg/ml
estrogen production in response to GnRHa challenge was
FT4 1.16 0.89-1.80 ng/dl increased (commensurate with tissue effects like advanced
TSH 2.48 0.35 –5.5 µIU/ml bone age, height age and firm breast consistency) as
LH 0.50 0.10-6.0 miu/ml compared to isolated thelarche but was lower (50%) of the
FSH 4.56 0.10-6.0 miu/ml
Testosterone 0.04 0.22-0.80 ng/ml
levels in true puberty(2). The authors postulated that, in this
DHEAS 63.50 14-266 µg/dl subset of precocious thelarche patients the substantial
Estradiol 10.0 10-36 pg /ml estrogen secretion is predominantly FSH driven. As FSH
axis is active in utero and during first few years of life the
Table 1b: 17-OHP levels after ACTH stimulation (250µg IV). condition may be due to delayed inactivation of the axis(8).
0 minutes 0.60 ng/ml The predominance of FSH secretion over LH may account
30 minutes 4.0 ng/ml for the self limited nature of the condition, as FSH alone is
60 minutes 4.20 ng/ml
unable to sustain ovarian maturation despite its known
stimulatory effect on ovarian aromatase activity(9). No more
Table 1c: LHRH stimulation test results (Triptorelin 100 µg i/v).
cases are documented in the literature subsequently and no
Time -30+ -!5+ 0 +15 +30 +45 +60 +90 +120 data about long term outcomes like height and gonadal status
LH UD UD 0.2 0.3 UD UD UD UD UD is known in these cases. Our case has clinical and biochemical
FSH UD UD UD 0.4 1.2 1.4 0.8 1.0 1.0 similar to the described cases and hence it substantiates the
existence of the condition and adds to the understanding that
The girl after a follow up of one and a half year showed sexual maturation also follows a spectrum.
no evidence of clinical or biochemical advancement in
secondary sexual characters and in fact the breast size REFERENCES
decreased. In view of the advanced bone and height age but 1. Mills JL, Stolley P D, Davies J, Moshang T. Premature
normal basal and dynamic endocrine evaluation, the thelarche.Natural history and etiological investigation. Am J Dis
Child 1981;135: 743-5.
thelarche was neither isolated nor part of sexual precocity 2. Stanhope R Brook CCD. Thelarche variant: a new syndrome of
(central or peripheral). Hence a diagnosis of exaggerated precocious sexual maturation? Acta Endocrinol (Copenh) 1990; 123:
thelarche was entertained. 481-6.
3. Garibaldi LR, Aceto T, Weber C. The pattern of gonadotrophin and
estradiol secretion in exaggerated thelarche. Acta Endocrinol
DISCUSSION 1993;128: 345-50.
4. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to
Isolated precocious thelarche commonly affects maturity for height, weight, height velocity and weight velocity:
females between 2-6 years (90% <2years) and most of these British children. Arch Dis Child 1966;41: 613-35.
are self limited. As the name implies it is not accompanied by 5. Tanner JM, Whitehouse RH, Cameroon N, Marshall W A, Healy
MJR, Goldstein H, eds. Assessment of skeletal maturity and
any menarche or advancement in height or bone age(1, 6). prediction of adult height (TW2 Method).London: Academic
Many a times the initial manifestation of a slowly progressive Press,1983.
variant of true central precocious puberty resembles isolated 6. Pasquino AM, Tebaldi L, Cioschi L, Cives C, Finocchi G et al
thelarche, the differentiation of these conditions is Premature thelarche: A follow up study of 40 girls -natural history
and endocrine findings. Arch J Dis Cild 1983;60: 1180-92.
important. Our case presented as thelarche but on clinical 7. Pescovitz OH, Hench KD, Barnes KM, Loriaux DL, Culler GP.
clues of advanced bone age and growth velocity a search for Premature thelarche central precocious puberty: the relationship
central precocious puberty was started. Contrarily basal and between clinical presentation and the gonadotrophin response to
dynamic endocrine evaluation was not suggestive of any leutenizing hormone-releasing hormone. J Clin Endocrinol Metab
1988;67: 474-9.
sexual precocity. LHRH stimulation test revealed an FSH 8. Winter JSD, Faiman C, Hobson WC, Prasad AV, Reyes FI. Pituitary
dominant response with undetectable E2. Hypothalamo- gonadal relations in infancy. Patterns of serum gonadotrophins
pituitary imaging was normal and follow-up revealed a self concentrations from birth to four years of age in man and
limited breast regression with no further skeletal chimpanzee. J Clin Endocrinol Metab 1975;40: 545-51.
9. Shoot DC, Herjan JT, Bennik C, Mannaerts B, Lambard I, Bouchard
advancement. On LHRH testing LH predominates in cases P et al. Human recombinant follicle-stimulating hormone induces
of true sexual precocity while as FSH predominates in the growth of preovulatory follicles without concomitant increase in
isolated thelarche subjects(7). Stanhope and Brook androgen and estrogen biosynthesis in a woman with isolated
enountered cases of sexual maturation whose LHRH gonadotrophin deficiency. J Clin Endocrinol Metab 1992;74: 1471-3.

40
IMAGES IN ENDOCRINOLOGY

A deformed humerus

Fig.1 Fig.2 Fig.3

A 31 yr man presented with pain in the right arm for
last six months. He had a fracture of right femur fixed with
nails and bone graft one year ago. Routine investigations
revealed a normal hematology, sugar, renal and liver
functions. His serum calcium was high [16.8 (corrected 16.2,
normal 8.6-10.2)mg/dl] with low serum phosphate [2.0
(normal 3.0-4.5) mg/dl] with raised ALP [363, (normal 53-
128) iu/ml] and Parathyroid Hormone 1258 (normal – 12-
72) pg/ml. Radiology of the right humerus showed a giant
osteolytic lesion (Fig. 1). An old X-ray of the same six months
back done elsewhere revealed severe osteopenia and
deformity (Fig. 2). CT scan neck and thorax revealed a
parathyroid adenoma with mediastinal extension (Fig. 3).
Surgery was done and the adenoma removed. Post-
operatively he developed hungry bone syndrome which was
managed with calcium infusion.

Sowmya U, Menaka R, Bhattacharyya A.

Department of Diabetes & Endocrinology, Manipal Hospital
98, Rustom Bagh, Airport Road, Bangalore, INDIA 560017
Tel: 00918025023404, Fax: 00918025266757
Email:arpan@diabetesendocrinology.in

41
IMAGES IN ENDOCRINOLOGY

Emphysematous pyelonephritis with emphysematous cystitis

in a young patient with diabetes and chronic calcific
pancreatopathy
A young man of 23 years presented to the Accident and
Emergency Department of the Sher-i-Kashmir Institute of
Medical Sciences, Srinagar with complaints of high grade
fever and occasional vomiting for the last 5 days. Previous
history revealed the patient to be a known case of insulin
dependent diabetes for the last 6 years. His laboratory
parameters revealed leucocytosis with random blood glucose
of 180 mg %.
Ultrasonography of the abdomen revealed high
reflectivity dirty shadows in the bilateral renal region with
acoustic shadowing. Similar dirt shadowing was also
observed in the bladder area. On non-contrast CT there was
extensive destruction of the bilateral kidneys which were
largely replaced with gas. The gas was also present in the
bilateral perinephric spaces, collecting systems and renal The patient died on the fifth day of admission.
parenchyma (Fig. 1 ). CT of the pelvis revealed presence of Emphysematous pyelonephritis is a rare and severe
extensive gas collection within the urinary bladder (Fig. 2). form of renal infection where gas is formed within the renal
parenchyma. Extension into the perirenal tissues, renal sinus
and collecting system may also occur(1). A significant
proportion of patients are diabetics(2). This condition has
also been described in transplanted kidneys(3). Organisms
found include E. coli, Klebsiella, Proteus and Aerobacter(1 ).
Less commonly Candida and Cryptococcus infection may
occur in diabetics(4).
There is high mortality associated with emphyse-
matous pyelonephritis and response to antibiotics alone may
be poor. Early nephrectomy has been recommended for
diabetics(4). However, this option could not be exercised in
our patient since he had bilateral renal affection.

Pancreas revealed multiple parenchymal and ductal
calcifications with mild prominence of the main pancreatic
duct. These findings were diagnostic of emphysematous
pyelonephritis, emphysematous cystitis and chronic
pancreatitis. The patient was managed with antibiotics and
other supportive measures. Surgical option could not be
considered since the patient had bilateral renal involvement.
REFERENCES
1. Allen HA, Walsh JW, Brewer WJ, et al. Sonography of emphysematous
py.elonephritis. J Ultrasound Med 1984; 3: 533.
2. Saunders AJS. Renal infections. In, Abdominal and General
Ultrasound vol 2: eds: Cosgrove D, Meire H, Dewbury K. Churchill
Livingstone, New York 1993.
3. Evaloff GV, Thompson CS, Foley R, Wienmann EJ. Spectrum of gas
within kidney: emphysematous pyelonephritis and emphysematous
pyelitis. Am J Med 1987; 8: 149.
4. Cook DJ, Achong MR, Dobranowski J. Emphysematous
pyelonephritis. Complicated urinary tract infection in diabetes.
Diabetes Care 1989; 12: 229.

Sanjeed Ahmed*, Irfan Robbani*, Sheikh Riyaz Rasool*, Nazir A. Khan**

Department of Radiodiagnosis* & Radiation Oncology**
Sher-i-Kashmir Institute of Medical Sciences, Kashmir, India.

42
 Instructions to Authors
All manuscripts must be prepared in accordance with “Uniform
requirements for Manuscripts submitted to Biomedical Journals”
developed by International Committee of Medical Journal Editors (Oct
2004). Before sending a manuscript contributors are requested to check
for the latest instructions available. The requirements for Indian Journal
of Endocrinology and Metabolism are summarized below
The Editorial Process
The manuscripts will be reviewed for possible publication with the
understanding that they are being submitted to one journal at a time and
have not been published, simultaneously submitted, or already accepted
for publication elsewhere.
All manuscripts received will be duly acknowledged, however the journal
will not return the unaccepted manuscripts. The Editors will review all
submitted manuscripts initially. Manuscripts with insufficient
originality, serious scientific flaws, or absence of importance of message
face chances of rejection. Other manuscripts will be sent to two or more
expert reviewers without revealing the identity of the contributors to the
reviewers. Each manuscript will be assigned to a member of the editorial
team, who based on the comments from the reviewers will take a final
decision on the manuscript and accordingly contributors will be
informed about the reviewers’ comments and acceptance/rejection of
manuscript.
Articles accepted would be copy edited for grammar, punctuation, print
style, and format. Page proofs will be sent to the first contributor, which
has to be returned within one week. Correction received after that period
may not be included.
Manuscripts
Review articles: Systemic critical assessments of literature and data
sources. Up to 4500 words excluding references and abstract. Up to three
reviews can be accepted per issue.
Original articles: Randomized controlled trials, intervention studied,
studies of screening and diagnostic test, outcome studies, cost
effectiveness analyses, case-control series, and surveys with high response
rate. Up to 3500 words excluding references and abstract.
Short communication: Brief studies involving trials, interventions,
outcome studies, analyses, case-control series, and surveys. Up to 2000
words excluding references and abstract.
Case reports: New/interesting/very rare cases can be reported. Cases with
clinical significance or implications will be given priority. Up to 1200
words excluding references and abstract and up to 12 references.
Letter to the Editor: They should not be preliminary observations that
need a later paper for validation but should be short and decisive
observations. Up to 500 words and 4 references.
Announcements of conferences, meetings, courses, awards, and other
items likely to be of interest to the readers should be submitted with the
name and address of the person from whom additional information can be
obtained. Up to 100 words can be allowed.
Authorship Criteria
Authorship credit should be based only on substantial contributions in
1) Conception and design or acquisition of data or its analysis and
interpretation
2) Drafting the article or revising it critically for important intellectual
content; and
3) Final approval of the version to be published.
Conditions 1, 2, and 3 must all be met. Each contributor should have
participated sufficiently in the work to take public responsibility for
appropriate portions of the content. The order of naming the contributors
should be based on the relative contribution of the contributor towards
the study and writing the manuscript.
For a case-report, Letter to the Editor and review article the number of
contributors should not exceed four. A justification should be included, if
the number of contributors exceeds these limits.
Preparation of the Manuscript
The text of observational and experimental articles should be divided
into sections with the headings: Introduction, Material and Methods,
Results, Discussion, References, Tables, Figures, Figure legends, and
Acknowledgment. Do not make subheadings in these sections. Send laser
printout, on white thick paper, of A4 size (212 × 297 mm), with margins of
25 mm (1 inch) from all the four sides. Type or print on only one side of the
paper. Use double spacing throughout. Number pages consecutively,
beginning with the title page. The header should contain running title
and the first author’s last name.
Title Page
The title page should carry
1) Type of manuscript (e.g. Original article, Case Report)
2) The title of the article, which should be concise, but informative;
3) Running title or short title not more than 50 characters;
4) The name by which each contributor is known (Last name, First
name and initials of middle name), with his or her highest academic
degree(s) and institutional affiliation;
5) The name of the department(s) and institution(s) to which the work
should be attributed;
6) The name, address, phone numbers, facsimile numbers and e-mail
address of the contributor responsible for correspondence about the
manuscript;
7) The total number of pages, total number of photographs and word
counts for the text (excluding the references and abstract);
8) Source(s) of support in the form of grants, equipment, drugs, or all of
these;
9) Acknowledgement, if any;
Abstract Page
The second page should carry the full title of the manuscript and an
abstract (of no more than 150 words for case reports, short
communication and 250 words for original articles). Below the abstract 3
to 10 key words should be provided.
Introduction
State the purpose of the article and summarize the rationale for the study
or observation.
Methods
The Methods section should include information about the plan or
protocol for the study, selection and description of participants like age,
sex, race or ethnicity, methods, apparatus (give the manufacturer’s name
and address in parentheses), and procedures in sufficient detail to allow
other workers to reproduce the results. Reports of randomized clinical
trials should present information on all major study elements, including
the protocol, assignment of interventions (methods of randomization,
concealment of allocation to treatment groups), and the method of
masking (blinding), based on the CONSORT Statement (Moher D,
Schulz KF, Altman DG: The CONSORT Statement: Revised
Recommendations for Improving the Quality of Reports of Parallel-
Group Randomized Trials. Ann Intern Med. 2001; 134:657-662).
Ethical considerations
When reporting experiments on human subjects, indicate whether the
procedures followed were in accordance with the ethical standards of the
responsible committee on human experimentation (institutional or
regional) and with the Helsinki Declaration of 1975, as revised in 2000.
Do not use patients’ names, initials, or hospital numbers, especially in
illustrative material. When reporting experiments on animals, indicate
whether the institution’s or a national research council’s guide for, or any
national law on the care and use of laboratory animals was followed.
Results
Data are summarized in the Results section, give numeric results not only
as derivatives (for example, percentages) but also as the absolute numbers
from which the derivatives were calculated, and specify the statistical
methods used to analyze them. Restrict tables and figures to those needed
to explain the argument of the paper and to assess its support. Use graphs
as an alternative to tables with many entries; do not duplicate data in
graphs and tables. Present your results in logical sequence in the text,
tables, and illustrations, giving the main or most important findings first.
Do not repeat in the text all the data in the tables or illustrations;
emphasize or summarize only important observations.
Discussion
In this section give summary of key findings (primary outcome measures,
43
secondary outcome measures, results as they relate to a prior hypothesis);
Strengths and limitations of the study (study question, study design, data
collection, analysis and interpretation); Interpretation and implications
in the context of the totality of evidence (is there a systematic review to
refer to, if not, could one be reasonably done here and now?, what this
study adds to the available evidence, effects on patient care and health
policy, possible mechanisms); Controversies raised by this study; and
Future research directions (for this particular research collaboration,
underlying mechanisms, clinical research).
Acknowledgments
As an appendix to the text, one or more statements should specify 1)
contributions that need acknowledging 2) acknowledgments of technical
help; and 3) acknowledgments of financial and material support, which
should specify the nature of the support.
References
References should be numbered consecutively in the order in which they
are first mentioned in the text by Arabic numerals in bracket. Use the style
of the examples below, which are based on the formats used by the NLM
in Index Medicus. Use complete name of the journal for non-indexed
journals. For scientific articles, contributors should obtain written
permission and confirmation of accuracy from the source of a personal
communication.
Articles in Journals
1. Standard journal article: Plazzo FF, Sadler GP, Reene TS. Minimally
invasive parathyroidectomy. BMJ 2004; 328:849-50. ( List the first
six contributors followed by et al).
2. Issue with supplement: Payne DK, Sullivan MD, Massie MJ.
Women’s psychological reactions to breast cancer. Semin Oncol
1996; 23(1, Suppl 2):89-97.
Books
3. Chapter in a book: Phillips SJ, Whisnant JP. Hypertension and
stroke. In: Laragh JH, Brenner BM, editors. Hypertension:
pathophysiology, diagnosis, and management. 2nd ed. New York:
Raven Press; 1995. pp. 465-78.
Tables
— Tables should be self-explanatory and should not duplicate textual
material.
— Type or print out each table with double spacing on a separate sheet
of paper.
— Number tables, in Arabic numerals, consecutively in the order of
their first citation in the text and supply a brief title for each.
— Place explanatory matter in footnotes, in non-standard
abbreviations that are used in each table.
— Obtain permission for all fully borrowed, adapted, and modified
tables and provide a credit line in the footnote.
Illustrations / Figures
— Send three sets, sharp, glossy, un-mounted, colour photographic
prints, with height of 4 inches and width of 6 inches.
— Figures should be numbered consecutively according to the order in
which they have been first cited in the text.
— Each figure should have a label pasted on its back indicating the
number of the figure.
— Titles and detailed explanations should be given in the legends for
illustrations not on the illustrations themselves.
— If photographs of people are used, either the subjects must not be
identifiable or their pictures must be accompanied by written
permission to use the photograph.
— If a figure has been published, acknowledge the original source and
submit written permission from the copyright holder to reproduce
the material. A credit line should appear in the legend for figures for
such figures.
Legends for Illustrations
Type or print out legends for illustrations using double spacing, with
Arabic numerals corresponding to the illustrations.
When symbols, arrows, numbers, or letters are used to identify parts of the
illustrations, identify and explain each one in the legend.
20
44
Sending the Manuscript
Please send three copies of the manuscript along with a covering letter,
contributors’ form signed by all the contributors, checklist and floppy in a
heavy-paper envelope. Place the photographs in a separate heavy-paper
envelope. The covering letter must include
1) A statement of financial or other relationships that might lead to a
conflict of interest, if that information is not included in the
manuscript itself or in an authors’ form.
2) A statement that the manuscript has been read and approved by all
the authors, that the requirements for authorship as stated earlier in
this document have been met.
3) The manuscript is neither published nor is under consideration for
publication elsewhere.
4) The name, address, and telephone number of the corresponding
author, who is responsible for communicating with the other
authors about revisions and final approval of the proofs.
5) Copies of any permission(s) to reproduce published material, and to
use illustrations or report information about identifiable people
must accompany the manuscript.
6) The manuscript should be sent to Indian Journal of Endocrinology
and Metabolism, Department of Endocrinology Sher-i-Kashmir
Institute of Medical Sciences Srinagar, Post Box 930, G.P.O.
Srinagar, Kashmir, INDIA.
E-mail: ashrafendo.ijem@gmail.com; ashrafendo@rediffmail.com
Electronic Version
— The manuscript must be accompanied by a CD containing the
manuscript.
— Use a new diskette or fully format the diskette before use. There
should be no other document, file, and material on the diskette other
than the final manuscript. Text, references, tables and legends, all
should be in one electronic file.
— Label each diskette with first contributor’s name, short title of the
article, software (e.g. MS Word), version (e.g. 7.0) and file name.
Name the file on the diskette with the corresponding contributor’s
last name (up to eight characters) and a three-letter extension to
signify the format (e.g. baruah.doc. Use any word-processing
program (e.g. Microsoft Word, Word Perfect) or provide text files.
— Use single space between lines for the manuscript on the floppy.
Provide the tables and charts at the end of the manuscript.
Sending a revised manuscript
While submitting a revised manuscript, contributors are requested to
include, along with single copy of the final revised manuscript, a
photocopy of the revised manuscript with the changes underlined in red
and copy of the comments with the point to point clarification to each
comment. The final revised manuscript should also be sent by e-mail to
ashraf.endo.ijem@gmail.com. The manuscript number should be written
on each of these documents.
Checklist (send one copy attached with the manuscript)
Covering letter
— Signed by all contributors
— Source of funding mentioned
— Conflicts of interest disclosed
Authors
— Author for correspondence, with e-mail address provided
identity not revealed in paper except title page (e.g. name of
the institute in Methods, citing previous study as ‘our study’,
names on figure labels, name of institute in photographs, etc.)
Manuscript
— Introduction, Material Methods, Results, Statistical analysis, Ethical
considerations, discussion and references.
Tables, figures and Legends
— Appropriately prepared
CD ROM
— If submitting hard copies
 Indian Journal of Endocrinology & Metabolism
OFFICIAL JOURNAL OF ENDOCRINE SOCIETY OF INDIA
I
EDITORIAL BOARD
Editor-in-Chief Associate Editor
Abdul Hamid Zargar Nikhil Tandon
Department of Endocrinology Department of Endocrinology & Metabolism
SKIMS, Srinagar AIIMS, New Delhi

Executive Editor
Mohd. Ashraf Ganie
Department of Endocrinology
Sher-i-Kashmir Institute of Medical Sciences, Srinagar
Editorial Board
Usha Shriram(Chennai) Ambrish Mital (New Delhi)
A.K. Bhansali (Chandigarh) S.K. Singh (Varanasi)
R.V. Jayakumar (Kottayam) Dinesh Dhanwal (New Delhi)
Padma Menon (Mumbai) Shashank R. Joshi (Mumbai)
Meena Desai (Mumbai) Ramesh Goyal (Ahamedabad)
R.K. Marwaha (New Delhi) R. Goswani (New Delhi)
Advisory Board
Ammini A.C. (New Delhi) D. Maji (Kolkata)
R.J. Dash (Chandigarh) S. Dutta Choudry (Guwhati)
P.S.N. Menon (Kuwait) R. Khardori (Chicago USA)
K. M. Suryanarayan (Banagalore) C.M. Batra (New Delhi)
Nalini Shah (Mumbai) C. V. Harinarayan (Tirupati)
Jamal Ahmad (Aligarh) Paresh Dandona (Buffalo, USA)
Sudakar Rao (Detroit, USA) Manash Barua (Guwahati)
Maryam Razagghi (Tehran, Iran) Subash Kukreja (Chicago, USA)
M.L. Khurana (New Delhi) Bilal Malik (USA)
A.M. Nadru (New York) Meenu Garg (New York, USA)
Tariq Shah (Detroit, USA) R.P. Kudyar (Jammu)
Chris Cowell (Australia) S. Kamili (Atlanta, USA)
A.K. Ajmani (New Delhi) B. A. Laway (Srinagar)
R. Murlidharan (Chandigarh) S. H. Khan (Srinagar)
M. I. Bashir (Srinagar)

Aims & Scope

The Indian Journal of Endocrinology & Metabolism (IJEM) the official journal of Endocrine Society of India is a quarterly published journal which
publishes original research articles, reviews, brief communication, case reports and images in endocrinology. We hope with the co-opertion and
guidance from members of Endocrine Society of India and other well wishers, the the journal will fast be enlisted in Pubmed & Index medicine.
Copy right & Photocopying
Papers accepted automatically become the copyright of IJEM. Single photocopies of single articles made for personal use is allowed by national
copyright laws. Permission by the editor/publisher is required for all other photocopying including multiple or systematic copying, copying for
advertisements or promotional purposes, resale, and all forms of document delivery
Disclaimer
The papers contained in each issue of the journal have been prepared and written by named authors. Accordingly, neither the Endocrine Society of India
or the IJEM, nor their officers, employees or agents are responsible for the accuracy or otherwise of any papers and shall have no liability for any claims,
damages or losses however arising from the contents of any papers or any use to which they may be put by any person.
Indian Journal of Endocrinology & Metabolism
I
Contents

EDITORIAL
Benefits of metformin in infertility of polycystic ovary syndrome 1 - 2
Mohd. Ashraf Ganie, Abdul Hamid Zargar

ORIGINAL ARTICLE
Prevalence and etiology of male hypogonadism 3 - 5
M Eunice, M.L. Khurana, N Gupta, K. Kucheria, A.C. Ammini

Ketonuria and Ketonemia in type 2 diabetes mellitus patients 7 - 9

attending an indian endocrine OPD
Sanjay Kalra, Bharti Kalra, Amit Sharma

The Prognostic Significance of thyroid antibodies in patients with 11 - 13

hyperthyroidism treated with Carbimazole
Sandip Kumar Batabyal, Sundip Chatterjee

REVIEW ARTICLES
Iodine supplementation: Benefits vs Concerns 15 - 21
Gopalakrishnan Sripathy , Marwaha Raman Kumar

Pheochromocytoma – revisited 23 - 29
KA Wani, Ajaz Ahmad Malik, Zahoor Ahmed Naikoo

UPDATE ARTICLE
Adiponectin in Health and Disease 31 - 34
Mohammad Hayat, Manzoor Ahmad

CASE REPORTS
Management of macroprolactinomas in Pregnancy- Report of two cases 35 - 37
B Kulshreshtha, VP Jyotsna, A Kriplani, Sonesh Kumar, A Seith, AC Ammini

Exaggerated Thelarche - an uncommon presentation of sexual maturation 39 - 40

Ashiq Masood, Ibrahim Masoodi, Abdul Rashid Shah, Sobia Nisar, Junaid Yaseen, M Ashraf Ganie

IMAGES IN ENDOCRINOLOGY
A deformed humerus 41
Sowmya U, Menaka R, Bhattacharyya A

Emphysematous pyelonephritis with emphysematous cystitis in a 42

young patient with diabetes and chronic calcific pancreatopathy
Sanjeed Ahmed, Irfan Robbani, Sheikh Riyaz Rasool, Nazir A. Khan

INSTRUCTIONS TO AUTHORS 43 - 44
 For manuscript submission and & Subscription
Contact:
Dr. Mohd. Ashraf Ganie
Department of Endocrinology & Metabolism
Sher-i-Kashmir Institute of Medical Sciences, Srinagar
Post Box 930, G.P.O. Srinagar, Kashmir - INDIA
Phone: 0194-2435712 / 0194-2401351 ext: 2064
E-mail: ashrafendo.ijem@gmail.com; ashrafendo@rediffmail.com
Website: http://www.endosocietyindia.com/
 Indian Journal of Endocrinology & Metabolism
I OFFICIAL JOURNAL OF ENDOCRINE SOCIETY OF INDIA

Endocrine Society of India (2006 - 2007)

OFFICE BEARERS

President
M. V. Murlidharan

President Elect Vice-President

A.C. Ammini Ambrish Mithal

Secretary Treasurer
Ganapathi B Yageesh Ayyar

Executive Committee Members

Sanjay Badada
G.S. Reddy
Mukhopadhya S
Keswani P
Rakesh Sahay
Unnikrishnan A G

The Endocrine Society of India is a non-profit organization established to promote clinical Endocrinology in India. Its
major objectives are to promote communication between all who are interested in endocrinology, involved in care of
patients with endocrine diseases and to advance research and education in Endocrinology.