( 1 )

INTRODUCTION

Menorrhagia is a frequent debilitating symptom in gynaecological practice

resulting in need for repeated curettage and hysterectomy with it's attendant

morbidity and mortality. The etiology of menorrhagia is very diverse, it may be

due to systemic conditions like endocrine disorders (usually hypothyroidism and

hyperthyroidism), or local lesions of the genital tract like endometrial hyperplasia,

pelvic inflammatory disease, endometriosis, benign tumors (leiomyoma, polyps)

and malignant tumors (endometrial carcinoma). In more than half of the subjects

the cause is not apparent.

Thyroid dysfunction is one of the common causes of excessive menstrual

blood loss and menstrual irregularities. Menorrhagia has been reported in 32%

(Means 1948) and in 32.4% (Wg Cdr S Sampath, Col P Singh, BL Somani , Col

MM Arora, Lt Col HS Batra, Lt Col AK Harith, V Ambade, MJAFI 2007; 63 : 233-

236.) of subjects with myxoedema. It may also lead to anovulation, infertility and

recurrent abortion. The onset of hypothyroidism is so insidious that classic clini-

cal manifestations may take months and years to appear (Ingbar 1985). Further-

more menorrhagia may be the only presenting complain in hypothyroid women

(Wilansky and Greisman 1989).

Sub-clinical thyroid dysfunction may go unnoticed by unwary clinicians as

these patients do not exhibit clinically overt physical symptoms and signs. This

may lead to avoidable surgical interference and related complications. With the

advent of modern techniques the estimation of various hormones in blood is

( 2 )

possible in rapid and reliable manner. The diagnosis of various endocrine disord-

ers can be easily made and medical treatment can be properly instituted. The re-

sults are usually very gratifying as patient is virtually symptom free on adequate

treatment.

Only few reports of study of thyroid functions in menstrual irregularities are

available from India. Mukherji and Ghosh (1984) reported low serum thyroxine

(T4) and tri-iodothyronine (T3) levels and normal levels of serum thyroid stimulat-

ing hormone (TSH) in patients with menorrhagia.

Menstrual and reproductive history of 178 women referred to the thyroid

clinic was compared with 49 healthy controls by JV Joshi, SD Bhandarkar, M

Chadha, D Balaiah, R Shah (1993), Only 31.8% of hypothyroid women had nor-

mal menstrual pattern in contrast with 87.8% of healthy controls (p < 0.001). The

prevalence of hypothyroidism in menorrhagia and polymenorrhea was 16.67%.

It has been stated that menorrhagia is more common in hypothyroidism or

myxoedema, Whilst anovulation or oligomenorrhoea is common in hyperthyroid-

ism. The relative frequency and type of menstrual disorders and the chronology

of the onset of reproductive dysfunction with respect to the onset and type of thy-

roid disorder have not been well defined. It is common practice to investigate for

thyroid functions when goiter or clinical symptoms and signs are present.

Present study was carried out to evaluate the thyroid function in larger

group of patients who were planned for hysterectomy or in whom hysterectomy

had been done due to dysfunctional uterine bleeding.

( 3 )

AIMS & OBJECTIVES

Aims and objectives of our studies were as follows:-

1. Selection of dysfunctional uterine bleeding cases from all cases of abnor-

mal uterine bleeding planned for hysterectomy or in whom hysterectomy

had been done for dysfunctional uterine bleeding.

2. Evaluation of thyroid status (euthyroid, hypothyroid, or hyperthyroid) in

dysfunctional uterine bleeding cases.

3. To observed the fraction of dysfunctional uterine bleeding cases having

hypothyroid status.

( 4 )

REVIEW OF THE LITERATURE

The thyroid (Greek - Thyreos, shield plus eidos form) is a circumscribed

gland of internal secretions whose functions is elaboration, storage and dis-

charge of a hormone which is principally concerned with the regulation of meta-

bolic rate.

The history pertaining to thyroid has been admirably summarized by Rol-

leston (1940). According to the formers account, Gallen in his De Voice briefly

described the gland. Vexalius in 1543 was first to give full description but it was

not till 1956 that organ was named the thyroid or oblong shield by Wharton.

The role of the gland in the body was subject of pleasant and interesting

speculation. Wharton suggested that the gland was there to round out and beau-

tify he neck "particularly in females to whom longer gland has been assigned",

others suggested it is lymphatic gland and a lubricant organ for larynx. Even as

late up to 1884, the gland was proposed "Vascular Shunt" cushioning the brain

against increased blood flow.

The morphological evidence of internal secretions was first offered by

King in 1836, who showed that some colloid of thyroid gland passed in to lym-

phatics and from there in to circulation. More detailed study of thyroid secretions

came in to the view after Bayliss and Starling coined the term hormone in 1902.

The relationship between thyroid and various body functions were studied by

experimental thyroidectomy. The association of iodine in functioning of thyroid

( 5 )

gland was described in 1896 by Braumann who discovered high concentration of

this element within the gland. Gkyand Bownet (1900) identified presence of or-

ganic iodine in plasma in combination with serum protein with crystallizations of

L-thyroxine from alkaline hydrolysates of thyroid tissue. Harrington and Barger

(1926) described the chemical structure of thyroxine.

Gross and Pitt-Rivers in 1954, identified a compound with only three

iodine atoms, tri-iodothyronine in gland and plasma. This compound proved to

be physiologically more potent and more rapid onset of action than thyroxine.

ANATOMY OF THYROID GLAND

As described by Williams (1985) in his review on thyroid, one of the larg-

est endocrine gland, is a brownish red, highly vascularised organ situated ante-

riorly in the neck at the level of fifth, sixth and seventh cervical and first thoracic

vertebrae. It normally weights 25-30 g or 3 - 3-1/2 g/kg body wt. varying with

age, sex, weight, status and habitation.

Its shape is like letter 'H' and consists of two lateral lobes and a connect-

ing isthmus. Each lobe is approximately 2.0 - 2.5 cm in both, thickness and width

at its largest diameter and is approximately 4.0 cm in length while the isthmus

measures 2 x 2 x 5 cms. The right lobe is more vascular than left and tends to

enlarge more in disorders associated with diffuse enlargement of thyroid.

The thyroid is closely affixed to the anterior and lateral aspects of trachea

by loose connective tissue along the lower half of lateral margins of thyroid carti-

lage. The upper margin of isthmus lies just below the cricoid cartilage.

( 6 )

Two main pairs of vessels contribute to the major arterial supply. The su-

perior thyroid arteries arising from external carotids and inferior thyroid arteries

arising from subclavian arteries, enter their respective poles. The veins drain in

corresponding veins. The approximate blood flow is 4-6 ml/min/kg. It receives its

nerve supply from both adrenergic and cholinergic nervous system, the former

arising from superior middle and inferior cervical ganglia while latter from laryn-

geal branches of vagus nerve.

On microscopy the gland is seen to be composed of closely packed sacs

called as acini or follicles. Each follicle is filled with the clear proteinaceous collo-

id, which constitutes the major thyroid mass. The average diameter of each fol-

licle is 200 µ and is lined by cuboidal cells becoming columnar when active,

while flat when inactive. The epithelium rests on basement membrane, which

separates follicular cells from the surrounding capillaries. 20-40 follicles sepa-

rated from each other by connective tissue, unite to form lobule, which is sup-

plied by a single artery.

In addition to the follicular cells, thyroid contains population of other cells,

variously termed parafollicular or c-cells, which secrete a calcium lowering pep-

tide, calcitonin.

PHYSIOLOGY OF THYROID GLAND

As described by Werner (1955) the primary function of thyroid gland is uti-

lization of iodine through a series of chemical changes by which complex com-

pounds are formed which influence the rate of cellular metabolism of the body.

( 7 )

Herrington (1939) stated that thyroid has specific affinity for iodine, which

enables it to utilize particularly all of this element which normally gains access to

the body. The iodine taken up by the thyroid is introduced in to tyrosine on thy-

roglobulin (also known as "organification of iodide") to form 3:4 di-iodotyrosine,

part of this is further converted in to thyroxine or triiodothyronine from two iodoty-

rosines. Thyroglobulin or colloid, constitutes the storage form of thyroid secre-

tion. The true thyroid secretion is in all likelihood a peptide containing both thy-

roxine and triiodothyronine and is liberated from thyroglobulin and released in to

blood stream in response to demands of the body.

SYNTHESIS OF THYROID HORMONES

The four steps in thyroid hormones synthesis are:-

1 Iodine - trapping/ Transport

2. Oxidation of iodides and organic iodination.

3. Coupling reaction of iodotyrosins

4. Storage and release of hormone

( 8 )

THE IODIDE CYCLE

(1) Iodide Transport

Formation of normal quantities of thyroid depends on availability of ade-

quate quantities of exogenous iodine. Normally iodine balance is maintained by

dietary sources i.e. food, water and via medication, diagnostic agents and use

of iodine, in food processing industries. Iodide absorbed from the gut enters in

the ECF, from there it is actively transported in thyroid follicular cells against

negative potential and then diffuses along the electrochemical gradient in to fol-

licular lumen, this biochemical mechanism is related to Na+ - K+, ATpase sys-

tem for phosphate bond energy. In addition, iodide is also generated in the thy-

roid gland by deiodination of iodotyrosines. A portion of this iodide is reorgani-

fied and remainder is lost from gland as so called 'Iodine PATHWAYS AND

IODINE METABOLISH

Total 25 mg Iodine in body 1/2 of it is in thyroid.

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½ in thyroid In blood in form of

Inogranic iodides-0.5µgm - 1gm/IOB

Protein bound iodine

Thyroxine

Tri-iodithyronine

α– globulin

Prealbumin

5 - 8 gm/100 ml

( 10 )

THYROID HORMONES SYNTHESIS BY FOLLICLE EPITHELIAL CELL

(2) Oxidation of Iodides and Organic Iodination:

Once trapped, the iodide is very rapidly changed in to activated form of

iodine. It results from peroxidase enzyme system which is present in thyroid. The

hydrogen peroxide which serves as an oxidant is generated through auto-

oxidation of flavin enzyme system acting as NADH - NADPH oxidases, oxidised

iodine is bound to tyrosines which exist as a part of thyroglobulin molecule and

form mono- iodotyrosines and di-iodotyrosines depending on no. of iodine atoms

in each tyrosine molecules. This step is conditioned by extent of thyroid stimula-

tion of TSH, Most of the anti thyroid drugs are inhibitory to this step.

(3) Coupling of Iodotyrosines:

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Formation of mono and di-iodotyrosines via oxidation and organic binding of

iodine, is followed by synthesis of hormonally active iodothyronines to yield the

structure with two di-iodinated rings linked by other bridge. Concomitantly there

occurs a loss of alanine side chain from ring that ultimately contains phenolin hy-

droxyl group. The reaction is termed as coupling reaction.

The tri-iodothyronine is formed by coupling of MIT and DIT. These iodotyro-

sines are held in a peptide bond within the thyroglobulin molecule and for coupling

of two peptide bonds iodotyrosines require disruption of peptide bonds, thus sub-

stantial change in thyroglobulin structure. Lack of TSH and iodine deficiency im-

pairs the synthesis of iodothyronines.

(4) Storage and release of Hormones

The thyroid gland is unique among endocrine glands by virtue of large

stores of hormones and slow overall rate of hormone release.

Organic iodine is constituted as MIT 17-28%, DIT 24-42%, T4 -35%, T3 -

6.8% and T4: T3 ratio is 10:1.

Thyroglobulin is the storage forms of thyroid hormones. T3 and T4 are libe-

rated in to circulation directly after their liberation from thyrogloblin by proteolytic

cleavage within the follicular cells, under stimulation of TSH follicular colloid enters

the cell by pinocytosis and attaches to lysosomes to form phagolysosomes, in

which thyroglobulin is hydrolysed, by proteases and peptidases thus liberate T3

and T4 . These hormones then diffuse through the wall of the follicle and reach the

( 12 )

blood stream, where they are degraded by enzyme dehydrogenase and iodine

remains available as second pool of for renewed oxidation and organic binding .

TRANSPORT TURNOVER AND METABOLISM OF THYROID HORMONE

A wide variety of iodothyronines and their metabolic products exist in plas-

ma, important ones are L-thyroxine (T4) , Leothyronines (T3) and reverse T3. Of

these T4 is in highest concentration (80%) and T3 (20%) is formed mainly by peri-

pheral mono-de-iodination of T4. Upon entering in plasma major secreted products

are bound in a firm, but reversible bond to several proteins, all of which are syn-

thesized in liver.

Two plasma proteins to which T4 is mainly associated are

- T4 binding - globulin (TB)

- T4 binding prealbumin (TBPA)

- To a limited extent albumin.

T3 is mainly bound to TBG and to a small extent albumin but not to TBPA.

T4 exist in plasma in bounded and free form. TBG is mainly responsible for trans-

port of T4 -(77%) and 0.03% is found in free form. T3 has low affinity for TBG and

mainly found in free form 0.30% (10 fold of T4).

Exact site of their peripheral breakdown is not known but they are metabo-

lised by de-iodinase enzyme and liberated iodides return to iodide pool. 80% of

thyroxine is metabolised in this manner and form 35% of T3.

( 13 )

Excretion occurs via biliary route (25% faecal excretion), through urine and

remaining iodine is returned to thyroid. Daily turnover of T4 in the periphery is

about 10% with half life of 6-7 days while daily turnover of T3 and rT3 is 60%.

Table 1 : Approximate values of plasma concentration, clearance rate and

production rate of thyroid hormones.

Compound Plasma Con. MCR 4 days Production rate

g/day

T4 8000 1 60

T3 120 25 30

rT3 25 120 30

3, 3T2 - 600 -

TBG 2 mg/dl 800 ml/day 16 mg/day

TBPA 25 mg/dl - 500 mg/day

THYROID STIMULATING HORMONE

Thyroid stimulating hormone is a glycoprotein of approximately 30,000 dal-

tons secreted by the anterior pituitary gland. TSH contains two non identical sub-

units termed as α and β. α subunits are similar in structure but β subunits differ

markedly in amino acid sequences and are responsible for biological specificity of

pituitary glycoprotein hormones. TSH induces production and release of thyroxine

and tri-iodothyronine from thyroid gland.

Levels of TSH are primarily controlled by thyrotropin releasing hormone

(TRH), secreted by hypothalamus and by negative feedback mechanism involving

( 14 )

serum concentrations of T4 and T3 as well as other less well defined mechan-

isms.

REGULATION OF THYROID FUNCTIONS

As with the other endocrine organs, thyroid participates with hypothalamus

and pituitary in a classic type of feedback control. In addition, intrinsic auto regula-

tory mechanisms create an increased relationship between glandular organic

iodine and rate of hormone production. These two controlling systems play role in

thyroid regulation.

1. Hypothalamo-pituitary-thyroid complex.

2. Thyroid auto regulation.

-

-

+

( 15 )

A potential role of sympathetic nervous system in regulation of thyroid hor-

mone function was recognized many years ago. Nerves originating from cervical

ganglia and vagus nerve terminate within the thyroid, both vascular and nonvas-

cular structures including thyroid follicles, receive adrenergic fibers.

Catecholamines influence various aspects of thyroid gland metabolism and

hormone biosynthesis in vitro. Epinephrine via α – receptor causes:

Increased iodine uptake by augmenting organification.

Stimulation of iodothyronine synthesis.

Increased glucose metabolism and protein synthesis.

but have no effect on degradation of iodoproteins. Both epinephrine and norepi-

nephrine inhibit TSH induced thyroid hormone release by α-receptor activation.

Catecholamines via β2 receptor exert no effect in animals with intact TSH secre-

tion but following suppression of it, increase thryoid hormone secretion. Thus phy-

siological significance of sympathetic nerves in regulation of thyroid is unclear.

PHYSIOLOGICAL ACTIONS OF THYROID HORMONE.

Thyroid hormone acts by stimulation of the RNA synthesis by binding to

specific receptor sites at nuclear chromatin. This increases protein and enzymes

responsible for various functions of thyroid hormones which are as follows:

1. Calorigenic action

Stimulates oxygen consumption and heat production in all tissues. After thy-

roidectomy, BMR is reduced by 40%.

(2) Growth

( 16 )

Thyroid hormones are essential for intrauterine as well extrauterine growth

and tissue differentiation. Intra uterine deficiency leads to cretinism while extra

uterine deficiency causes characteristic epiphyseal dysgenesis.

(3) Metabolic actions

(a) In physiological doses they are anabolic and stimulates protein syn-

thesis but in high doses produce catabolism i.e. thyrotoxicosis.

(b) They increase the glucose absorption from the gut, rate of its intracel-

lular entry and its utilization. Large doses cause glycogenolysis.

(c ) They increase the rate of cholesterol synthesis in the liver, rate of its

biliary excretion, its conversion to bile acids, and faecal loss.

(4) Cardiovascular system

Thyroxine is a positive chronotrophic as well as ionotrophic to heart. It partly

acts directly and partly by sensitizing it to effect of catecholamines.

(5) Central Nervous System

Thyroxine is essential for myelination of nerves. In higher concentration

causes irritability, tremors, hyperkinesias, while decreased concentration causes

mental retardation, decreased tendon reflexes and convulsions.

(6) Gastrointestinal tract

Diarrhoea and constipation are commonly seen in hyper and hypothyroid-

ism respectively.

Achlorhydria is commonly associated with both.

( 17 )

(7) Reproductive tract and breasts

Gonadal functions are disturbed in both sexes in hyper- and hypothyroid-

ism, in females lead to precocious puberty, menstrual irregularities, Anovulation

and infertility, Hirsutism, Galactorrhoea.

Thyroxine is a potent galactopoetic hormone.

(8) Haemopoetic systems

Incidence of megaloblastic anaemia is increased in hypothyroidism.

(9) Skin Changes

Thyroxine deficiency causes deposition of muco-polysaccharides in connec-

tive tissues causing roughness of skin.

(10) Miscellaneous

Creates wasteful creatinuria

Various myopatheis and paralysis

Defective conversion of carotine & vit A deficiency state.

FACTORS AFFECTING THYROID HORMONE ECONOMY

The widespread metabolic role of thyroid hormones, the diverse processes

involved in their synthesis, secretion and metabolism indicate that many factors

can influence thyroid hormone economy. In general these factors are:-

1. Endogenous variables.

2. Pharmacological agents

3. Environmental alterations

( 18 )

4. Dysfunction and diseases of other organ system.

The important factors out of these are:-

Age

Environmental temperature

Nutritional influence

Sex and sex hormones

Pregnancy and newborn states

Non thyroidal illness

Stress acting through adrenergic nervous system

THYROID DISEASE AND REPRODUCTIVE DYSFUNCTION

Thyroid disorders have been implicated in broad spectrum of reproductive

disorders ranging from abnormal sexual development to menstrual irregularities

and infertility. Thyroid dysfunction may influence reproductive system in variety of

ways ranging from Hirsutism, galactorrhoea, precocious puberty, delayed puberty

and menstrual irregularities.

Hypothyroidism and hyperthyroidism both have been implicated as underlying

cause of many irregularities of menstruation i.e. Menorrhagia, menometrorrhagia,

intermenstrual spotting, polymenorrhoea, oligomernorrhoea, amenorrhoea and

hypomenorrhoea. In severe cases of hypothyroidism continuous and severe blood

loss has also been reported.

Clinical experience shows that increased menstrual flow to be most com-

mon reproductive system manifestation of hypothyroidism. Severe hypothyroidism

( 19 )

may result into menorrhagia, intermenstrual bleeding or continued and severe

blood loss.

This present study has been undertaken to evaluate the thyroid function in

women presenting with various menstrual irregularities menorrhagia, menome-

trorrhagia, intermenstrual spotting and polymenorrhoea in whom no organic cause

is detectable on clinical examinations, are planned for hysterectomy or hysterect-

omy has been done for menstrual irregularities.

Since the incidence of hypothyroidism is greater in women than in man

[(Degroot, Stanbury 1975 - Adult Hypothyroid states and myxoedema. In thyroid

and its disease p405 New York John Wiley and Sons (1975)], and hypothyroidism

affects reproductive system in women more than in men, thyroid function studies

are usually indicated in the evaluation of aforesaid conditions in gynaecological

practice.

HUMAN STUDIES

Development of genital tract

Reproductive tract appears to develop normally in cretins, implying hypothy-

roidism developing during foetal life does not appear to affect the normal devel-

opment of reproductive tract (Pharoah 1980).

Sexual Development

Hypothyroidism in prepubertal years generally leads to short stature and

may lead to delay in sexual maturity (Hayles 1972).

( 20 )

Kunde et al (1980) have reported precocious menstruation and galactorr-

hoea in girls with juvenile hypothyroidism. It is usually thought that there is an

overlap in pituitary production of TSH and gonadotrophins resulting in early ova-

rian stimulation. Ovarian stimulation results in estrogen production and endome-

trial stimulation with vaginal bleeding. Prolactin levels are usually elevated leading

to galactorrhoea. However, there is no pubertal increase in adrenal production of

androgen precursors so that axillary and public hairs are not apparent. Therapy

with thyroxine in adequate dosage results into prompt alleviation of symptomatol-

ogy.

MENSTRUAL PATTERN IN THYROID DISEASE

In adult women hypothyroidism results in changes in cycle length and

amount of bleeding, some patients also present with amenorrhoea and galactorr-

hoea.

Means (1948) noted menorrhagia in 32 per cent of 41 premenopausal pa-

tients with myxoedema.

Gardner Hill and Smith (1927) and Lerman (1950) independently reported

the incidence of menorrhagia in 80% of myxoedema patients.

Goldsmith et al (1952) studied menstrual pattern ovulation and endometrial

biopsy in 10 patients with primary myxoedema and found that 5 had metropathia

haemorrhagica, 2 had menorrhagia, 1 had amenorrhoea and 2 had normal pe-

riods. Seven patients showed no evidence of ovulation. Endometrial biopsy

( 21 )

showed proliferative endometrium which reversed to secretory after starting the

treatment.

Reported incidence of menorrhagia varies from 32 to 80 per cent (Ross et

al 1958).

Ross et al (1958) reported 2 cases of profuse uterine bleeding secondary to

unrecognized primary myxoedema in which prompt cessation of uterine bleeding

and restoration of normal menstrual cycle followed the oral administration of des-

sicated thyroid.

Praschis et al (1958) reported that amenorrhoea may follow after thyroi-

dectomy but menorrhagia is more common.

Reis and Decosta (1961) expressed the opinion that myxoedema does not

result in typical aberration of menstrual cycle and stated that bleeding may be ex-

cessive, acyclic or diminished.

Scott and Elizabeth Mussey (1964) reported menstrual disturbances in 56%

of 50 cases of myxoedema. In 5 patients the bleeding was sufficiently abnormal to

dilatation and curettage of uterus but in no instance malignant disease was found.

Wilanskyand Griesman (1989) studied thyroid functions in 67 apparently

euthyroid menorrhagia women by thyrotropin releasing hormone test and

found exaggerated response of thyrotropin toTSH in 15 patients. All patients

responded to replacement therapy (Wilansky and Griesman 1989). Only few

reports of study of thyroid functions in menstrual irregularities are available

from India. Mukherji and Ghosh (1984) reported low serum thyroxin (T4) and

( 22 )

tri-iodothyronine (T3) levels and normal levels of serum thyroid stimulating

hormone (TSH) in patients with menorrhagia.

Menstrual and reproductive history of 178 women referred to the thyroid clinic

was compared with 49 healthy controls by JV Joshi, SD Bhandarkar, M Chad-

ha, D Balaiah, R Shah (1993) Only 31.8% of hypothyroid women had normal

menstrual pattern in contrast with 87.8% of healthy controls (p < 0.001). The

prevalence of hypothyroidism in menorrhagia and polymenorrhea was

16.67%.

In another study conducted by Wg Cdr S Sampath, Col P Singh, BL Somani

, Col MM Arora, Lt Col HS Batra, Lt Col AK Harith and V Ambade (2007), menorr-

hagia has been reported in 32.4% of patients with myxoedema

HYPOTHYROIDISM

Pathogenesis of menorrhagia in hypothyroidism is still a speculation, it is

probably due to defect in uterine muscle contraction (Ross et al 1958) or a direct

effect of deficient thyroid hormones on endometrial response to estrogen.

Hypothyroid women have a decrease in sex hormone binding globulin of

testosterone and there is increase in metabolic clearance rate of testosterone

(Gordon and Southern 1977).

Hypothyroidism also results into altered peripheral metabolism of oestro-

gen. An increased rate of 16 -Alpha hydroxylation of estradiol in hypothyroidism

results into increased formation of estriol. This altered oestrogen may result in ab-

normal feedback at the pituitary level with aberrant release of gonadotrophins re-

( 23 )

sulting in chronic anovulation along with excessive unopposed action of estrogen

on endometrium producing menstrual irregularities (Gordenet al 1977).

Hyperprolactinaemia may be associated with hypothyroidism as increased

production of thyrotropin releasing hormone in these cases could readily account

for hyper secretion of TSH and PRL which lead to anovulation and menstrual irre-

gularities (Honbo et al 1978).

Kramer et al (1979) reported that hypothyroidism alone without hyperprolac-

tinaemia may directly interfere with normal hypothalamo-pituitary-overian function

resulting in menstrual dysfunction. In less severe cases of hypothyroidism me-

norrhagia is common. This may result from chronic unopposed oestrogenic stimu-

lation, causing a cyclic shedding of endometrium and episodes of menorrhagia.

Contreras et al (1981) have demonstrated loss of usual PRL rise after ad-

ministration of dopamine antagonist in long standing primary hypothyroidism.

Thus decreasing synthesis on secretion of dopamine in hypothalamus could ac-

count for loss of dopaminergic inhibitory influence on PRL, TSH and LH. This

hyperprolactinemia resulting from long standing primary hypothyroidism has been

implicated in ovulatory dysfunction and menstrual irregularities.

RESPONSE OF MENSTRUAL IRREGULARITIES TO THERAPY IN HYPO AND

HYPERTHYROIDISM

Goldsmith et al (1952) reported in 17 patients of thyrotoxicosis that in all,

menstrual irregularities improved rapidly with the treatment of thyrotoxicosis with

( 24 )

antithyroid drugs. Ross et al (1958) reported successful treatment of severe me-

norrhagia by replacement therapy in 2 myxoedematous patients.

Mambru et al (1978) reported that menstrual disorders associated with

classical primary hypothyroidism responded to administration of L-thyroxine.

Wilensky et al reported that menorrhagia disappeared within 3-6 months

and did not reappear in1 to 3 years follow up in all patients of early hypothyroidism

to whom L-thyroxine was given (Wilansky et al 1989).

( 25 )

MATERIAL AND METHODS

This study was carried out in 50 patients selected from OPD/IPD in De-

partment of Obstetrics and Gynaecology and Post Graduate Department of Medi-

cine, S.N. Medical College and Hospital, Agra.

SELECTION OF CASES

In our series both outdoor admitted patients were included. These patients

were randomly divided into groups. these groups were

1 Menorrhagia

2 Menometrorrhagia

3 Intermenstrual spotting

4 Polymenorrhoea

The patients suspected of organic gynaecological disorder were excluded

from the present study. Age of the patient varied between 20-40 years.

CLINICAL EXAMINATION

After recording name, age, caste, duration of menstrual problem, age of

menarche, menstrual pattern both present and past, obstetric history, age of last

child birth, an attempt was made to obtain history suggestive of endocrine dys-

function and past history of intake of antithyroid drugs.

A thorough clinical examination of patient was done on following lines.

( 26 )

GENERAL AND SYSTEMIC EXAMINATION

The general body built, height, weight, pulse, BP respiratory rate, pallor, ic-

terus, cyanosis, clubbing, oedema lymphadenopathy. body temperature, eye

signs, hairs, skin changes were noted.

Cardiovascular system, respiratory system, central nervous system and ab-

domen were thoroughly examined. The thyroid gland was examined for any ab-

normality.

GYNAECOLOGICAL EXAMINATION

Complete gynaecological examination (P/S and P/V) was done with the

help of female resident doctors to rule out any organic gynaecological disorder.

Following points were noted on P/S and P/V examination.

P/S:- 1. Condition of vagina/discharge

2. Cervix:

a. Hypertrophy

b. Congestion

c. Discharge

d. Direction

e. Erosion

P/V:- 1. Uterus

a. Size - Normal

( 27 )

Bulky (more than normal but not 6 > wks. enlarged multiparous

size)

b. Consistency of uterus

c. Direction of uterus

d. Mobility of uterus

e. Tenderness of uterus

2. Fornices

a. Tender/Nontender

b. Adnexa - Palpable/not palpable.

INVESTIGATIONS

Routine investigations for blood haemoglobin, total and differential

count, biochemical and microscopic examination of urine were done etc.).

DIAGNOSTIC CRITERIA

After thorough clinical examination, the patients having dysfunctional

uterine bleeding (menorrhagia, menometrorrhagia, polymenorrhoea, or inter-

menstrual spotting), who were planned for hysterectomy or in whom hyste-

rectomy had been done for dysfunctional uterine bleeding, were selected and

subjected to routine haematological investigations along with their T4,TSH es-

timation.

INCLUSION CRITERIA

( 28 )

Multipara women having menstrual irregularities between 20-40 years

of age were included in the study.

Only those patients, in whom organic causes (fibroid, leiomyoma etc.) of

menstrual irregularities were excluded by clinical examination along with

appropriate investigations, were selected for the study.

The patient in whom hysterectomy had been done for dysfunctional ute-

rine bleeding, were also included in study after analyzing their previous

medical records.

EXCLUSION CRITERIA

Women <age of 20, because of peripubertal confounding factors

and>40 years of age because of perimenopausal confounding factors,

were excluded from the study.

Patients, in whom structural causes of menstrual irregularities was

found.

Patients, in whom hysterectomy had been done for reasons, other than

dysfunctional uterine bleeding.

Patients, in whom thyroid had been resected or underwent radiation

therapy in past.

Patients on treatment for hyperthyroidism (iatrogenic).

( 29 )

Patient who were taking drugs which might cause abnormal results on

thyroid function tests (Amiadarone,Lithium, Phenytion etc.).

GROUING OF PATIENTS

Patients were divided into four groups.

Age group in all the cases ranged between 20-40 yrs. (child bearing age).

Group A - Included twenty patients having, complaints of excessive

bleeding in amount and duration - menorrhagia.

Group B - Included fifteen patients having complaints of excessive bleed-

ing along with spotting in between the menstruation-

Menometrorrhagia.

Group C - Ten patients having complaints of excessive bleeding along

with short cycles - Polymenorrhea.

Group D - Five patients having complaints of bleeding or spotting in be-

tween the menstruation - Intermenstrual spotting

SAMPLE COLLECTION AND PREPARATION

Sera were prepared from a whole blood specimen obtained by acceptable

medical techniques. Kit was used with serum samples without additives. Speci-

mens were capped and stored for up to 48 hours at 2-8°C prior to assay.

ESTIMATION OF TOTAL THYROXINE LEVEL

( 30 )

Principle of the test

In the T4 EIA, a certain amount of anti-T4 antibody is coated on microtiter

wells. A measured amount of patient serum and a constant amount of T4 conju-

gated with horseradish peroxidase are added to the microtiter wells. During incu-

bation, T4 and conjugated T4 compete for the limited binding sites on the anti- T4

antibody. After 60 minutes incubation at room temperature, the wells are washed

5 times by water to remove unbound T4 conjugate. A solution of TMB is then add-

ed and incubated for 20 minutes, resulting in the development of blue color. The

color development is stopped with the addition of 2 N HCl, and the absorbance is

measured spectrophotometrically at 450 nm. The intensity of the color formed is

proportional to the amount of enzyme present and is inversely related to the

amount of unlabeled T4 in the sample. By reference to a series of T4 standards

assayed in the same way, the concentration of T4 in the unknown sample is quan-

tified.

MATERIALS AND COMPONENTS

Materials provided with the test kits:

Antibody-coated microtiter wells. 96 wells per bag.

Reference standard set, ready to use.

T4 HRPO Conjugate Diluent, 15 ml.

T4 HRPO Conjugate Concentrate, 0.8 ml

TMB Substrate, 12 ml.

( 31 )

Stop Solution, 12 ml.

Materials required but not provided:

Precision pipettes: 40μl~200μl and 1.0ml

Disposable pipette tips.

Distilled water.

Vortex mixer or equivalent.

Absorbent paper or paper towel.

Graph paper.

Microtiter well reader.

Storage of test kits and instrumentation

1. Unopened test kits were stored at 2-8°C upon receipt and the microtiter

plate were kept in a sealed bag with desiccants to minimize exposure to

damp air. The test kit might be used throughout the expiration date of the kit

(One year from the date of manufacture), once opened.

2. A microtiter plate reader at 450nm wavelength was used in absorbance

measurement.

Reagent preparation

1. All reagents were brought to room temperature (18 - 22°C) before use.

2. To prepare T4 -HRPO Conjugate Reagent, 0.1 ml of T4 -HRPO Conjugate

Concentrate was added to 2.0 ml of T4 Conjugate Diluent (1:20 dilution),

and mixed well.

( 32 )

Assay procedures

1. Desired number of coated wells were secured in the Holder and data sheet

was made with sample identification.

2. 50 μl of standard, specimens, and controls were dispensed into appropriate

wells.

3. 100μl of Enzyme Conjugate Reagent was dispense into each well.

4. Thoroughly mixed for 10 seconds.

5. Incubated at room temperature (18-22°C) for 60 minutes.

6. The incubation mixture was removed by flicking plate contents into a waste

container.

7. The microtiter wells were rinsed and flicked 5 times with running tap water.

8. The wells were stroke sharply onto absorbent to remove all residual water

droplets.

9. 100μl of TMB solution was dispensed into each well and Gently mixed for 5

seconds.

10. Incubated at room temperature for 20 minutes without shaking.

11. By adding 100μl of Stop Solution to each well the reaction was stopped.

12. Optical density at 450nm was read with a microtiter well reader.

Calculation of results

1. The average absorbance values (A450) for each set of reference stan-

dards, control, and samples were calculated.

( 33 )

2. A standard curve was constructed by plotting the mean absorbance ob-

tained for each reference standard against its concentration in μg/dl on li-

near graph paper, with absorbance on the vertical (y) axis and concentra-

tion on the horizontal (x) axis.

3. Using the mean absorbance value for each sample, the corresponding con-

centration of T4 in μg/dl was determined from the standard curve.

Example of standard curve

Results of typical standard run with optical density reading at 450nm shown

in the Y axis against T4 concentrations shown in the X axis.

.

T4 (μg/dl) Absorbance (450nm)

0 3.217

1 2.465

2.5 1.961

5 1.331

15 0.746

30 0.436

( 34 )

0 10 20 30 40

T4 concentration (microg/dl)

0

2

4

6

8

10

12

14

16

OD

REFERENCE RANGE AND SENSITIVITY

Normal range was 5.0 to 13.0 μg/dl. The minimum detectable concentration

of thyroxine by this assay was 0.4μg/dl.

ESTIMATION OF TSH

Principle of the test

This test is based on a monoclonal antibody-sandwich to ensure an optimal

sensitivity and specificity. The wells are coated with a monoclonal antibody di-

rected against a unique antigenic site on the TSH molecule. The microtiter strips

are incubated with patient samples and enzyme conjugate, which is a horseradish

peroxidase-conjugated monoclonal antibody directed against a different antigenic

determinant of the TSH molecule. The amount of immune complexes bound to the

wells is in proportion to the TSH concentration in the samples. After washing off

( 35 )

the unbound serum proteins and conjugate molecules, the strips are incubated

with chromogen solution and a blue colour develops in proportion to the amount of

immune complexes bound to the wells.

REAGENTS

1. Microwell strips : wells coated with mouse anti-TSH monoclonal antibody

(96 wells).

2. Enzyme conjugate : horseradish peroxidase conjugated monoclonal antibo-

dies to TSH (12 ml), red coloured.

3. Chromogen Solution: buffer solution containing hydrogen peroxide and te-

tramethyl-benzidine (25 ml).

4. Reference Standard Set: 1ml equine serum containing 0,05 – 0,25 - 1 - 5

and 12 μIU/ml TSH. (WHO 2nd IRP 80/558).

5. Specimen Diluent and Zero Standards: equine serum with antimicrobial

agents (5 ml).

MATERIALS REQUIRED BUT NOT SUPPLIED

1. A microtiterplate reader.

2. Precision micropipettes with tips for 50 μl, 100 μl and 1000 μl.

3. Shaker for microtiterplates.

4. Stopping Solution: 12 ml 2N H2SO4.

ASSAY PROCEDURE

General remarks

( 36 )

1. All reagents and specimens were allowed to come to room temperature be-

fore the test was started.

2. All steps were completed without interruption.

3. All reagents and samples were pipetted onto the bottom of the well.

4. All specimens and standards were running in duplicate concurrently so that

all conditions of testing were the same.

5. Manual pipetting of all standards, controls and samples were completed

within 3 minutes.

Procedure

1. Desired number of coated wells were secured in the holder and data sheet

was marked with sample identification.

2. 100 μl of standards or serum was dispensed to the appropriate wells.

3. 100 μl of enzyme conjugate was added to each well.

4. The microtiter strips were incubated for 30 min. at room temperature on a

microtiter plate shaker (500 rpm).

5. The contents of the strips were briskly shaken out.

6. The wells were rinsed 5 times with distilled or water.

7. 150 μl of the chromogen solution was added.

8. The microtiter strips were incubated for 30 min. at room temperature.

9. The enzymatic reaction was stopped by adding 50 μl of stopping solution

(2N H2SO4) to each well.

( 37 )

10. The absorbance of each well was determined at 450 nm within 30 minutes

following step 9.

RESULTS

The microtiter plate reader capable of determining the absorbance at 450

nm was used. The TSH value of each patient was obtained as follows :

1. The average absorbance values obtained for each reference standard (or-

dinate) was plotted against the TSH concentration (abcis) and the best cali-

bration curve (e.g. log/log) was constructed.

2. The average absorbance of each patient sample was used to determine the

corresponding TSH concentration from this standard curve.

REFERENCE RANGE.

Normal range 0.4-6.1µIU/dl,

Hyperthyroid <0.4 µIU/dl ,

Euthyroid 0.4-6.1 µIU/dl,

Hypothyroid >6.1 µIU/dl,

The minimal detectable concentration of TSH is estimated to be <0.04

μIU/ml by this method.

( 38 )

OBSERVATIONS

The material for the present study comprised of 50 patients with various

menstrual irregularities as follows :

1. Menorrhagia (Group A) - 20

2. Menometrorrhagia (Group B) - 15

3. Polymenorrhoea (Group C) - 10

4. Intermenstrual spotting (Group D) - 5

AGE DISTRIBUTION

TABLE 1 : Age distribution among group A, B, C, D

Group No. of case Mean + SD Range

A 20 31.3 + 5.59 20 – 38

B 15 32.13 + 3.44 25 – 36

C 10 32.7+ 4.78 22 – 40

D 5 35.6 + 0.49 35 – 36

Table1: shows age distribution of patients. There was no significant differ-

ence in age among the various groups.

( 39 )

TABLE 2 : Age of Menarche in various groups

Group Mean + SD Range

A 10.69 + 2.05 11 – 14

B 12.80 + 0.68 12 – 14

C 12.50 + 0.71 12 – 14

D 12.20 + 0.84 11 – 13

The age of menarche in all the groups were similar to one another (Table

2).

TABLE 3 : Menstrual Pattern in Group A (Menorrhagia)

(n = 20)

Present Past

Duration (days) M + SD 8.85 + 1.07 3.95 + 1.10

Range 7 – 12 3 – 5

Cycle (days) M + SD 29.30 + 1.72 29.40 + 1.93

Range 25 – 32 25 – 30

Flow Increased Normal

p < 0.02

( 40 )

DURATION OF MENSTRUAL FLOW

0

1

2

3

4

5

6

7

8

9

10

A GROUPS B C D

DA

YS

PRESENT PAST

0

5

10

15

20

NU

MB

ER

A

GROUPS

B C D

AMOUNT OF MENSTRUAL FLOW

ADEQUATE INCREASED

( 41 )

Table 3: shows the pattern of menstrual cycle in group A. The duration of

menstruation and flow was significantly increased in these patients (Present : M

+ SD 8.85 + 1.07 days, Range 7 - 12, Past 3.95 + 1.10 days, Range 3 - 5 days

p < 0.02). yet, the duration of menstrual cycle was not significantly altered

(Present : M + SD 29.3 + 1.72 days, range 25 - 32 days, Past : M + SD 29.4 +

1.93 range 25 - 30 days, p > 0.05).

TABLE 4 : Menstrual Pattern in Group B (Menometrorrhagia)

(n = 15)

Present Past

Duration (days) M + SD 7.36 + 1.1 3.0 + 0.85

Range 5 – 9 2 – 5

Cycle (days) M + SD 27.6 + 7.22 30.8 + 0.36

Range 25 – 30 28 – 35

Flow Increased Normal

Table 4: shows the menstrual pattern in group B (Menometrorrhagia). The

duration of menstrual flow was significantly increased in all the subjects

(Present : M + SD 7.36 + 1.1 days, Range 5 - 9, Past 3.0 + 0.85 days, Range 2

- 5 days p < 0.01). The menstrual flow was markedly increased in all the sub-

jects. However, the duration of cycle was not significantly altered.

( 42 )

TABLE 5 : Menstrual Pattern in Group C (Polymenorrhoea)

(n = 10)

Present Past

Duration (days) M + SD 5.5 + 1.27 5.0 + 0.47

Range 5-9 4-6

Cycle (days) M + SD 17.5 + 2.64 30.2 + 1.14

Range 15-20 28-30

Flow Increased 9 0

Normal 1 10

p < 0.01 (t = 3.68)

Table:5 shows the menstrual pattern in group C (Polymenorrhoea). The

duration of cycle was significantly shorter in these subjects (Present : M + SD

17.5 + 2.64 days, Range 15 - 20, Past 30.2 + 1.14 days, Range 28 - 30 days p

< 0.01). The flow was increased in 9 patients (90%) while it remained normal in

one. The duration of flow remain unaltered.

TABLE 6 : Menstrual Pattern in Group D (Intermenstrual spotting)

( 43 )

(n = 5)

Present Past

Duration (days) M + SD 5.2 + 1.10 5.6 + 1.34

Range 4 – 7 5 – 8

Cycle (days) M + SD 29.2 + 1.10 32.0 + 2.84

Range 28 – 30 30 – 35

Flow Increased 1 0

Adequate 4 5

Intermenstrual

spotting

M + SD 4.2 + 0.83 -

Range 3 – 5 -

p < 0.01 (t = 4.2)

Table:6 shows the menstrual pattern in group D (Intermenstrual spotting).

The duration of flow and duration of cycle were not significantly altered but all of

these subjects had intermenstrual spotting (Present : M + SD 4.2 + 0.83 days,

Range 3 - 5, Past 0 days, Range 0 days p < 0.01)

( 44 )

TABLE 7 : Present Menstrual pattern in various groups.

Menstrual Pattern

Groups

A (20)* B (15)* C (10)* D (5)*

Duration of flow (days)

M 8.85 7.36 5.5 5.2

S.D. 1.07 1.1 1.27 1.10

Range 7 - 12 5 – 9 56 - 9 4 – 7

Duration of Cycle

M 29.3 27.6 17.5 29.2

S.D. 1.72 7.22 2.64 1.10

Range 25 - 32 25 – 30 15 - 20 28 – 30

Amount of Flow

Adequate NIL NIL 1 4

Increased 20 15 9 1

Diminished NIL NIL NIL NIL

Pain + 7 6 7 2

Clots + 12 4 8 1

* p < 0.05, ** p > 0.05

Table7: shows the comparison of the present menstrual pattern in various

groups.

The statistical analysis reveals that the duration of flow was significantly in-

creased in menorrhagia group and menometrorrhagia group as compared to their

previous values(p<0.05). In other groups (group C&D),the flow was not significant-

ly altered (p>0.05). The duration of cycles were significantly shorter in group C as

compared to their previous values (p<0.05) and the other groups (group A,B &D)

(p<0.05),while in others (groups A, B & D) the duration of cycle was not signifi-

cantly altered from their past values (p>0.05).

( 45 )

The amount of flow was increased in all the patients in group A and B, 9 pa-

tients (90%) in group C and 1 patient (20%) in group D.A good proportion of pa-

tients had dysmenorrhea and passage of clots in group A,B and C.

OBSTETRICAL PROFILE

TABLE 8: Obstetrical pattern in various groups.

Obstetrical Pattern

Groups

A (20) B (15) C (10) D (5)

Gravida M 2.95 3.4 2.7 3.8

S.D. 1.90 1.06 1.64 1.30

Range 0 - 6 2 – 6 1 - 4 3 – 6

Parity M 2.55 2.93 2.2 3.2

S.D. 1.67 1.22 1.03 0.84

Range 0 - 4 2 – 6 1 - 4 2 – 4

Abortion M 0.4 0.47 0.5 0.6

S.D. 0.75 0.64 0.85 0.80

Range 0 - 2 0 – 2 0 - 2 0 – 2

Abn. Labour 1 2 1 1

LCB (yrs.) M 4.68 6.2 4.5 3.2

S.D. 2.90 4.02 2.85 2.68

Range 2 - 10 2 – 12 2 - 10 1 – 2

The analysis of obstetrical pattern in all the groups revealed that the gravi-

da, parity, no. of abortions, number of abnormal labours and the last child birth

were similar to one another (Table 8).

( 46 )

CLINICAL GENERAL

TABLE 9: Pallor and edema in various groups

Group N Hb%

(mean)

Pallor Edema

A 20 9.25 19 Nil

B 15 10.00 9 1

C 10 9.45 9 1

D 5 10.50 4 2

None of the patients had history of post partum haemorrhage and failure to

menstruate following delivery. History of lactation was present following the deli-

very in all the subjects. In none of subject, there was a history of headache, vomit-

ing and visual deficit (suggestive of pituitary tumour), pain in thyroid region (sug-

gestive of subacute thyroiditis), goitre, intake of iodine containing drugs (iodine

preparation, amiadarone, povidone iodine etc.), thyroid surgery, thyrotoxicosis

and radioactive iodine therapy).

All the patients had no history of edema over body, cold intolerance, consti-

pations, dry skin, hoarseness of voice, decreased appetite and dyspnoea. Exami-

nation revealed that all the patients and controls were clinically euthyroid accord-

ing to Wayne’s index and had no goitre. However, pallor was present in majority

of patients in group A, B, C and D (Table 9).

CLINICAL GYNAECOLOGICAL EXAMINATION

( 47 )

Clinical Gynaecological examination (per vaginum and per speculum) was

performed in all the patients. The findings on gynaecological examination are ta-

bulated in Table 10.

TABLE 10 : Gynaecological examination in various groups A, B, C and D. Groups Perspeculum Per Vaginum

Vagina Cervix Uterus

Fornices Size Consist. Mobility

Group A n = 19

Healthy 15 Healthy 9 N 9 Firm 19 Mobile 19 Clear 19

Discharge 4 Hypertrophy 6 Bulky 4 Soft 0

Erosion 3 6 wk 6

Congestion 5

Group B n – 15

Healthy 13 Healthy 9 N 7 Firm 15 Mobile 15 Clear 15

Discharge 2 Hypertrophy 2 Bulky 2 Soft 0

Erosion 2 6 wk 3

Laceration 1

Congestion 1

Group C n = 5

Healthy 6 Healthy 5 N 5 Firm 10 Mobile 10 Clear 10

Discharge 4 Hypertrophy 3 Bulky 3

Erosion 1 6 wk 2

Congestion 1

Group D n = 5

Healthy 4 Healthy 4 N 4 Firm 5 Mobile 5 Clear 5

Discharge 1 Hypertrophy 1 Bulky 1

HAEMOGLOBIN STATUS

TABLE 11 : Haemoglobin levels in group A, B, C and D

Groups

A (20) B (15) C (10) D (5)

Haemoglboins (g/dl)

M 9.52 10.0 9.45 10.5

S.D. 2.5 0.79 0.5 1.0

Range 8.5 - 10.5 8.5 - 10.8 9.0 - 10.5 9.2 - 13.5

Investigations revealed that blood haemoglobins level were lower in all the

patients.

THYROID FUNCTIONS

TABLE 12 : Thyroid functions in group A

( 48 )

Table12: shows thyroid functions among patients of Group A. One pa-

tients out of 20 was having thyroid functions suggestive of primary hypothy-

roidism 5% of total (TSH value 24.0 I μ U/ml, T4 -3.6 μ g/dl .

Group

A (n =

20)

T4

( g/dl)

TSH (

IU/ml)

Elevated Decreased %

Mean 7.52 3.7 n=1,TSH=24.0 N=1, T4=3.6 5%

SD 2.12 4.77

Range 3.6-12.5 1.0-24.0

( 49 )

SCATTER DIAGRAM OF GROUP A (MENORRHAGIA)

0

2

4

6

8

10

12

14

0 5 10 15 20 25

n=20

SE

RU

M T

HY

RO

XIN

E

(mic

rog/d

l)

SCATTER DIAGRAM OF RROUP A (MENORRHAGIA)

0

5

10

15

20

25

30

0 5 10 15 20 25

n=20

SE

RU

M T

SH

LE

VE

L (

mic

roIU

/dl

TABLE 13 : Thyroid functions in group B

( 50 )

Group

A (n =

20)

T4

( g/dl)

TSH (

IU/ml)

Elevated Decreased %

Mean 7.28 2.97 N=1,TSH=15.2 N=1 T4=2.1 6.67

SD 1.99 3.41

Range 2.1-10.5 0.8-

15.2

Table13: shows thyroid functions among Group B patients showing one pa-

tient with elevated serum TSH level. This shows 6.5% incidence of primary hypo-

thyroidism in this group.

( 51 )

SCATTER DIAGRAM OF GROUP B (MENOMETRORRHAGIA)

0

2

4

6

8

10

12

14

16

0 2 4 6 8 10 12 14 16

n=15

SE

RU

M

TH

YR

OX

INE

(mic

rog

/dl)

)

SCATTER DIAGRAM OF GROUP B (MENOMETRORRHAGIA)

0

2

4

6

8

10

12

14

16

0 2 4 6 8 10 12 14 16

n=15

SE

RU

M T

SH

(m

icro

IU/d

l)

TABLE 14 : Thyroid functions in group C

Group

C (n =

20)

T4

( g/dl)

TSH (

IU/ml)

Elevated Decreased %

Mean 6.49 2.7

SD 1.17 0.71

Range 5.1-8.7 1.1-4

( 52 )

Table 14 :shows the result of thyroid functions of group C patients patients in this

group were euthyroid . .

SCATTER DIAGRAM OF GROUP C (POLYMENORRHOEA)

0

1

2

3

4

5

6

7

8

9

10

0 2 4 6 8 10 12

n=10

SE

RU

M T

4 L

EV

EL

(MIC

RO

G/D

L)

SCATTER DIAGRAM OF GROUP C (POLYMENORRHOEA)

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

0 2 4 6 8 10 12

n=10

SE

RU

M T

SH

(mic

roIU

/dl)

TA-

BLE15 : Thyroid functions in group D

Group A

(n = 20)

T4

( g/dl)

TSH (

IU/ml)

Elevated Decreased %

Mean 9.32 2.0

SD 1.6 0.77

Range 7.3-12.0 0.8-3.1

( 53 )

Table15: shows thyroid functions in group D patients. All patients in this

group were euthyroid.

SCATTER DIAGRAM OF GROUP D (INTERMENSTRUAL

SPOTTING)

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6

n=5

SE

RU

M T

HY

RO

XIN

E(m

icro

g/d

l)

SCATTER DIAGRAM OF GROUP D (INTERMENSTRUAL

SPOTTING)

0

0.5

1

1.5

2

2.5

3

3.5

0 1 2 3 4 5 6

n=5

SE

RU

M T

SH

(m

icro

IU/d

l)

( 54 )

TABLE 16: Comparison of thyroid functions among group A, B, C and D

Group S. T4 ( g/dl) S.TSH ( IU/ml)

A Mean + S.D. 72.52 + 2.12 3.7 + 4.77

Range 3.6 - 12.5 1.0 – 24.0

B Mean + S.D. 7.28 + 1.99* 2.97 + 3.41*

Range 2.1 - 10.5 0.8 - 15.2

C Mean + S.D. 6.49 + 1.17* 2.7 + 0.71**

Range 5.1 – 8.70 1.1 – 4.0

D Mean + S.D. 9.32 + 1.6* 2.0 + 0.77**

Range 7.3- 120.. 0.8 – 3.1

* Intergroup comparison p > 0.05

** Intergroup comparison p > 0.05

Table16: shows intergroup comparison of thyroid levels. It shows that mean

serum T4 levels in group D are comparatively higher than in group A, B, C and se-

rum TSH levels in this group are lower than group A, B, C. This difference in le-

vels was not statistically significant.

( 55 )

DISCUSSIONS

Menorrhagia is a frequent debilitating symptom in gynecological prac-

tice resulting in need for repeated curettage and hysterectomy with its atten-

dant morbidity and mortality. Objective measurements have shown that mean

menstrual blood loss in each menstrual cycle is 35 ml and menstrual blood

loss is considered to be excessive when it is more than 80 ml per cycle (90th

percentile).

The aetiology of menorrhagia is very diverse. It may be due to systemic

conditions like hormonal imbalance (usually hypothyroidism and hyperthyroid-

ism), or local lesions of genital tract like endometrial hyperplasia, pelvic in-

flammatory disease, endometriosis, benign tumours (leiomyoma, polyps) and

malignant tumours (endometrial carcinoma). In more than half of the subjects

the cause is usually not apparent.

Thyroid dysfunction is one of the common causes of excessive men-

strual blood loss and menstrual irregularities. Menorrhagia has been reported

in 32% of subjects with myxoedema (Means 1948) and in 32.4% (Wg Cdr S

Sampath, Col P Singh, BL Somani , Col MM Arora, Lt Col HS Batra, Lt Col AK

Harith, V Ambade, MJAFI 2007; 63 : 233-236.) It may also lead to anovulation,

infertility and recurrent abortion. The onset of hypothyroidism is so insidious

that classic clinical manifestation may take months and years to appear (In-

( 56 )

gbar 1985). Furthermore menorrhagia may be the only presenting complain in

hypothyroid women (Wilansky and Greisman 1989).

With the advent of modern hormonal assay techniques precise estima-

tion of thyroid hormones in serum is possible in a rapid and reliable manner.

Treatment of hypothyroidism is very satisfying as it usually relieves patient of

all the symptoms. Hence in investigating a patients with menorrhagia and/or

menstrual irregularities, evaluation of thyroid functional status forms an essen-

tial component. Early detection of hypothyroidism in such subjects saves the

patient from recurrent curettage and at times hysterectomy.

We evaluated 50 patients with various menstrual irregularities and di-

vided into 4 groups, according to menstrual pattern. The age of these subjects

ranged from 20 – 40 years (Table 1). Thus excluding peri-menopausal men-

strual irregularities. Subjects in Group A (menorrhagia) had significantly in-

creased duration of flow in each menstrual cycle as compared to duration of

past menstrual flow (p < 0.02, table 2) though the cycles were regular and

length of cycles were not significantly altered (p > 0.05). Group B (meno-

metrorrhagia) had subjects with increased duration of menstrual flow as com-

pared to past menstrual pattern (p < 0.01, table 3) with regular menstrual

cycles but unpredictable bleeding off and on. These subjects differed from

subjects with intermenstrual spotting (Group D) as in the former, the amount

of flow in episodes of unpredictable menstrual flow was much more. Subjects

in group C (Polymenorrhoea) had significantly shortened cycles (p < 0.01 Ta-

ble 4) with unaltered duration of menstrual flow. Group D subjects (Intermen-

( 57 )

strual spotting) had unpredictable small bleeding per vaginum which was

much lesser than subjects of menometrorrhagia.

Comparison of the present menstrual pattern of various patient groups

(Group A, B, C and D) revealed that the patients in group A and B had signifi-

cant increase in duration of menstrual flow (Present VS Past : Group A M +

SD = 8.85 + 1.07 / 3.95 + 1.10, Group B M + SD = 7.63 + 1.1 / 3.0 + 0.85, p

< 0.05, Table 3 & 4). In group C and D the mean duration of flow was slightly

increased but it was not no significantly increased from the past (p > 0.05, Ta-

ble 7). The duration of menstrual cycle was significantly shorter in subjects

with polymenorrhea as compared to subjects in group A, B and D (Table 7).

The volume of menstrual flow was increased in all the patients in group A and

group B and in majority of subjects in group C. An analysis of obstetrical histo-

ry among all the patient groups revealed no significant difference suggesting

that past obstetrical history had no bearing on current menstrual pattern.

Detailed clinical evaluation was carried out to rule out any obvious en-

docrinal and gynaecological cause of menstrual irregularities. None of these

patients had evidence of hypothyroidism on clinical examination viz. hair and

kin changes, non-pitting oedema, obesity, bradycardia, delayed relaxation of

deep tendon reflexes, cerebellar signs. None of these patients had evidence

of enlarged, nodular, tender or firm thyroid gland. According to Wayne’s index

all the patients were clinically euthyroid with score less than 19, there was no

evidence of spontaneous or expressive galactorrhoea, in these patients.

( 58 )

Gynaecological examination were carried out by doing per speculum

and per vaginal examination to rule out any vaginal, cervical or uterine pathol-

ogy amounting for intermenstrual spotting, menorrhagia and polymenorrhea.

Routine haemogram revealed lower haemoglobin levels in all the pa-

tient groups.

An analysis of thyroid functions in all the patient groups revealed that

two patients had low levels of serum thyroxine and high levels of serum TSH,

suggesting primary hypothyroidism. One of these two patients, had menorrha-

gia and the other had menometrorrhagia. In the rest of the patient groups Se-

rum thyroxine and TSH were within a normal limits.

( 59 )

TABLE 1A: Comparison of thyroid functions among group A, B, C and D

Group Serum Thyrox-

ine ( g/dl)

Serum thyroid stimulat-

ing hormone ( IU/ml)

A Mean + S.D. 7.52 + 2.12* 3.7 + 4.77**

Range 3.6 – 12.5 1.0 – 24.0

B Mean + S.D. 7.28 + 1.99* 2.97 + 3.41**

Range 2.1 – 10.5 0.8 – 15.2

C Mean + S.D. 6.49 + 1.17* 2.7 + 0.71**

Range 5.1 - 8.70 1.1 – 4.0

D Mean + S.D. 9.32 + 1.6 2.0 + 0.77

Range 7.3- 120.. 0.8 – 3.1

* Intergroup comparison p > 0.05

** Intergroup comparison p > 0.05

Intergroup comparison of serum thyroxine and TSH revealed no signifi-

cant difference (p > 0.05, Table IA). Thus the prevalence of hypothyroidism in

our patients was 4%.

( 60 )

SERUM THYROXINE AND TSH IN

VARIOUS GROUPS

0

1

2

3

4

5

6

7

8

9

10

A

GROUPS

B C DME

AN

SE

RU

M L

EV

EL

S O

F T

4 A

ND

TS

H

SERUM THYROXINE SERUM T4

TABLE

2A: Comparison of serum T4 and TSH in present study to thyroid hormone

profile in study by Mukherji et al (1984)

Groups S. Thyroxine ( g/dl) S. Thyroid stimulating

hormone ( IU/ml)

Mean SD Mean SD

Menorrhagia

n = 8

Mukherji (1984)

3.1 0.50 1.2 0.26

Menorrhagia

(n = 20)

Present study

7.52 2.12 3.7 4.77

Menometrorrhagia n = 15

Present study

7.28 1.99 2.97 3.41

( 61 )

Only few reports of thyroid functions in menstrual irregularities are

available in the literature. Mukherji and Ghosh (1984) studied 8 patients of

menorrhagia and 10 patients of oligomenorrhoea / amenorrhoea. None of the

patients of menorrhagia had elevated serum TSH levels but they had subnor-

mal T4 and T3 levels. The finding of low T3 and T4 in the presence of low TSH

suggests hypothalamo-pituitary origin of hypothyroidism. However, the pa-

tients were not investigated further and there was not any mention of accom-

panying systemic illness like severe anaemia which can lead to sick euthyroid

syndrome in which the patients are clinically and metabolically euthyroid. 8 pa-

tients out of 10 patients with oligomenorrhoea and amenorrhoea had border-

line elevation of serum TSH (Mean + SD 4.8 + IU/L). In primary hypothyroid-

ism serum TSH levels are usually more than 15 IU/L.

TABLE 3A: Comparison of thyroid hormones profile in present study with

that of study by Wilansky (1989)

Groups S. Thyroxine

( g/dl)

S. Thyroid stimu-lating hormone

( IU/ml)

No. of Hypo-

thyroid patients

Significance

Mean SD Mean SD

Menorrhagia (n = 67) Wilansky et al

7.7 4.0 6.3 2.2 15 p < 0.01

Menorrhagia

(n = 20)

Present study

7.52 2.12 3.7 4.77 1 p > 0.05

Menometrorrhagia n = 15

Present study

7.28 1.99 2.97 3.41 1 p > 0.05

Wilansky and Griesman (1989) studied 67% apparently euthyroid me-

norrhagic women by a thyrotropin releasing hormone test. The baseline serum

( 62 )

thyroxine and tri-iodothyronine levels were normal in all the patients. 15 out of

67 patients showed mild primary hypothyroidism as evidenced by exaggerated

response of S.TSH to TRH administration test. Patients had significantly lower

serum T4 levels as compared to patients with normal TSH response to TRH

test. These patients with exaggerated response had disappearance of me-

norrhagia on L-Thyroxine replacement therapy. However, this study was car-

ried out in peripubertal girls.

Menstrual and reproductive history of 178 women referred to the thyroid

clinic was compared with 49 healthy controls by JV Joshi, SD Bhandarkar, M

Chadha, D Balaiah, R Shah (1993) Only 31.8% of hypothyroid women had

normal menstrual pattern in contrast with 87.8% of healthy controls (p <

0.001). The prevalence of hypothyroidism in menorrhagia and polymenorrhea

was 16.67%.

Pathogenesis of menorrhagia in hypothyroidism is still speculative. It is

probably a defect in uterine muscle contraction (Ross et al 1958) or a direct

effect of deficient thyroid hormone on the endometrial response to estrogen.

It may be due to oestrogen break through bleeding secondary to anovu-

lation. There is a decrease in sex hormone binding globulin which results in

increased metabolic clearance rate of testosterone (Gordon Southren 1977).

There is also altered peripheral metabolism of oestrogen. The precise altera-

tion in oestrogen metabolism and its neurohypophyseal control has not being

fully elucidated. Gorden et al (1977) had reported increased rate of 16-α- hy-

( 63 )

droxylation of estradiol resulting into increased formation of estriol, this altered

estrogen may result in abnormal feedback at hypothalamo-pituitary axis result-

ing into aberrant release of gonadotropins and chronic anovulation. This ex-

cessive unopposed action of oestrogen on uterine endometrium causes acyc-

lical shedding of endometrium and episodes of menorrhagia.

Hypothyroidism can also lead to hyperprolactinemia which may also

contribute to various menstrual irregularities (Honobo et al 1978).

Contreras et al (1981) have demonstrate loss of usual prolactin rise af-

ter administration of dopamine antagonists in long standing primary hypothy-

roidism, thus decreasing synthesis and secretion of dopamine in hypothala-

mus. This accounts for loss of dopamine inhibitory influence on PRL, TSH &

LH. This hyperprolactinemia resulting from long standing primary hypothyroid-

ism has been implicated in ovulatory dysfunction and menstrual irregularities.

The iodine deficiency is probably the commonest cause of hypothyroid-

ism in India and it may be questioned whether this could have contributed to

the genesis of hypothyroidism in our patients. It seems unlikely in view of the

absence of goiter in our patients and free availability of ionized salts in this

part of the country. However, urinary iodine excretion measurements are re-

quired to make a definitive statement. Among other causes of primary hypo-

thyroidism with normal sized thyroid gland is Hashimoto’s thyroiditis. Estima-

tion of serum thyroid microsomal antibody and antithyroglobulin antibody is

required to confirm it.

( 64 )

Serum TSH response to TRH test can diagnose patent primary hypothyroidism

(Wilansky and Griesman 1989). Prevalence of hypothyroidism in our patients

may have been higher if we had performed this test. We could not carry out this

investigation because of non-availability of TRH test facility.

TABLE 4A: Distribution of patients according to their TSH values.

TSH-µIU/ml Group-A Group-B Group-C Group-D %age of total

<0.4 0 0 0 0 0%

0.4-3.0 14 12 8 4 76%

3.0-6.1 5 2 2 1 20%

6.1-10.0 0 0 0 0 0%

>10.0 1 1 0 0 4%

( 65 )

0

2

4

6

8

10

12

14

DIS

TR

IBU

TIO

N O

F P

AT

IEN

TS

<0.4 TSH 0.4 - 3 3.0 - 6.1 6.1 - 10 >10

DISTRIBUTION OF PATIENTS ACCORDING TO THEIR TSH

VALUES

GROUP A GROUP B GROUP C GROUP D

0

1

2

3

4

5

6

7

FR

EQ

UE

NC

Y

A

GROUPS

B C D

FREQUENCY OF HYPOTHYROIDISM IN GROUPS

(A,B,C&D) ACCORDING TO CURRENT TSH RANGE

HYPOTHYROIDISM %

( 66 )

At present normal TSH range is 0.4-6.0 IU/ml, recently American clini-

cal endocrinologists proposed that normal range of TSH should be narrowed

from present 0.4-6.0 to 0.3-3.0 IU/ml as 95%of normal population fall in this

group, moreover 20 years follow up of the patients having TSH more than 3.0

IU/ml showed that majority of them converted to hypothyroid status later on.

If we follow these observations and guidelines 24% of our patients will

be out of range of normal, 4% will have hypothyroid status and 20% sub-

clinical hypothyroid status. These patients having sub-clinical hypothyroid sta-

tus should be followed closely because majority of them will be converted to

hypothyroid status in future.

There was no evidence of hyperthyroidism in our study population. We

did not measure serum T3 levels because T3 estimation is usually normal in

early hypothyroid states.

( 67 )

SUMMARY & CONCLUSION

The present study was carried out in 50 patients selected from

OPD/IPD in Department of Obstetrics and Gynaecology and Post Graduate

Department of Medicine, S.N. Medical College and Hospital, Agra.

The patients were categorized in four groups depending on the type of

menstrual irregularity.

(1) Group A (n=20) : Patients with menorrhagia.

(2) Group B (n=15): Patients with menometrorrhagia.

(3) Group C (n=10): Patients with polymenorrhoea.

(4) Group D (n=5): Patients with intermenstrual spotting. All

these patients were clinically evaluated in detail for any gynecological or clini-

cally obvious endocrinal cause of menstrual irregularity. All these patients

were clinically euthyroid as judged by Wayne’s index and had no goiter or any

other topographic abnormality of thyroid on clinical examination. All these pa-

tients were subjected to routine hematological investigations.

Serum thyroxin and thyroid stimulating hormone were estimated in sera

samples using commercially available ELISA kits.

The clinical observations and thyroid functions in various groups were

analyzed, statistically compared and following conclusions were drawn.

( 68 )

(1) Mean serum T4 and TSH levels in group A were 7.52 + 2.12 g/dl

(range 3.6-12.5 g/dl) and 3.7 + 4.77 IU/ml (1.0-24 IU/ml),one patient

had primary hypothyroidism as evidenced by low T4 (3.6 g/ml) and

high serum TSH levels (24 IU/ml).

(2) The mean serum T4 and TSH levels in group B were 7.28 + 1.99 /dl

(range 2.1-10.5 /dl) and 2.97 + 3.41 IU/ml (range 0.8-15.2 /ml). One

of the patients had evidence of primary hypothyroidism as evidenced by

low T4 (2.1 g/dl) and high serum TSH levels (15.2 UI/ml).

(3) All the patients in group C (polymenorrhea) and Group D (Intermen-

strual spotting) had normal serum thyroxine and TSH levels (group C :

T4 M + SD 6.49 + 1.17, range 5.1 - 8.7, TSH M + SD 2.7 + 0.71 range

1.1 - 4, Group D : T4 M + SD 9.32 + 1.6, range 7.3 - 12.0, TSH M + SD

2.0 + 0.77 range 0.8 - 3.1).

(4) In menorrhagia women the prevalence of hypothyroidism was 5% while

in subjects with menometrorrhagia, prevalence of hypothyroidism was

6.67%. The overall incidence of hypothyroidism in our study was 4%.

(5) All the patients of polymenorrhea and intermenstrual spotting were eu-

thyroid.

(6) There was no evidence of hyperthyroidism in our study population.

The diagnosis of thyroid dysfunction as a etiological factor in a small

portion of cases of various menstrual irregularities gives a new direction to the

( 69 )

medical management and it is well known that these patients respond dramat-

ically to appropriate thyroid replacement therapy. At present normal TSH

range is 0.4 - 6.0 IU/ml, recently American clinical endocrinologists proposed

that normal range of TSH should be narrowed from present 0.4 - 6.0 to 0.3 -

3.0 IU/ml as 95%of normal population fall in this group, moreover 20 years

follow up of the patients having TSH more than 3.0 IU/ml showed that majori-

ty of them converted to hypothyroid status due course of their follow up period.

Similarly in our study if we follow reference range of TSH 0.3 -3.0, 24%

of patients will be labeled as hypothyroid.

Therefore we propose that in all patients having menstrual irregularities

if no organic cause is found, thyroid function test should be done and a close

watch is needed in their follow up.

( 70 )

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