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TEXILA AMERICAN UNIVERSITY GUYANA 2152650158750021526501587500 Table of Contents INTRODUCTION3ORDER OF CONTENTS4COVER PAGE AND INSIDE TITLE PAGE5CERTIFICATE7DECLARATION8ACKNOWLEDGEMENT10DEDICATIONS12ABBREVIATIONS13TABLE OF CONTENTS14GENERAL INSTRUCTIONS15INTRODUCTION166SAMPLE166OBJECTIVE OF THE STUDY177HYPOTHESIS188REVIEW OF LITERATURE200MATERIALS AND METHODS222RESULTS AND DISCUSSION244SUMMARY277CONCLUSION2929 CONTRIBUTION TO KNOWLEDGE300SUGGESTION FOR FUTURE RESEARCH322REFERENCES333APPENDIX366LIST OF PUBLICATIONS BASED ON THE THESIS377 INTRODUCTION This document intended to provide a set of specific and uniform guidelines for the preparation of the thesis

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TEXILA AMERICAN UNIVERSITY
GUYANA
2152650158750021526501587500
Table of Contents
INTRODUCTION3ORDER OF CONTENTS4COVER PAGE AND INSIDE TITLE PAGE5CERTIFICATE7DECLARATION8ACKNOWLEDGEMENT10DEDICATIONS12ABBREVIATIONS13TABLE OF CONTENTS14GENERAL INSTRUCTIONS15INTRODUCTION166SAMPLE166OBJECTIVE OF THE STUDY177HYPOTHESIS188REVIEW OF LITERATURE200MATERIALS AND METHODS222RESULTS AND DISCUSSION244SUMMARY277CONCLUSION2929
CONTRIBUTION TO KNOWLEDGE300SUGGESTION FOR FUTURE RESEARCH322REFERENCES333APPENDIX366LIST OF PUBLICATIONS BASED ON THE THESIS377
INTRODUCTION
This document intended to provide a set of specific and uniform guidelines for the preparation of the thesis. It is also imperative that the thesis, be acceptable by the University, should essentially meet a uniform format emphasizing readability, concordance with ethical standards and University-wide homogeneity. For the convenience of the reader the Guidelines are separated into various parts for easy understanding.

This document also provides the working templates for the students for better understanding and they can use the same format in their thesis with necessary corrections or alterations wherever needed.

In preparation of the thesis or dissertation, the researcher is expected to have novelty, originality in the research carried and in expressing them in documentation process. Plagiarism is highly offended and is subjected to disqualification of the award of the degree. Plagiarism is usually defined as copying or paraphrasing from others without reference to the source. Plagiarism in a thesis is completely unacceptable. Plagiarism an act or instance of using or closely imitating the language and thoughts of another author without authorization and the representation of that author’s work as one’s own, as by not crediting the original author.

ORDER OF CONTENTS
The thesis has to be organized in the following order:
Cover Page
Inside Title Page
Certificate signed by the Supervisor(s) (in the stipulated format)
Declaration signed by the Candidate (in the stipulated format)
Acknowledgements
Dedications (if any)
Abbreviations (if any)
Table of Contents
Introduction
Review of Literature
Materials and Methods
Results and Discussion
Summary
Conclusion
Contribution to knowledge
Suggestion for Future Research
References
Appendix (if any)
List of Publications based on the thesis

Thyroid disorder in dysfunctional uterine bleeding

DISSERTATION
Submitted to Texila American University in partial fulfillment of the requirement for the award of the Degree of MS in Endocrinology.

Submitted by
Dr. Syed Kashif Ahsan
Under the Guidance of
Dr. Prof Dr Waris kudwai
TEXILA AMERICAN UNIVERSITY
GUYANA
centercenter
DECLARATION
I, Syed Kashif Ahsan declare that this thesis entitled Thyroid disorder in dysfunctional uterine bleeding submitted in partial fulfillment of the degree of MD / MS is a record of original work carried out by me under the supervision of Prof Dr Waris kudwai. In keeping with the ethical practice in reporting scientific information, due acknowledgements have been made wherever the findings of others have been cited.

5220970195580
Signature
Syed Kashif Ahsan
Name of the candidateDate

ACKNOWLEDGMENTS
I take this opportunity to thank, Prof Dr Waris kudwai Dean R &D, Research Committee members, member secretary, members of Thesis guidelines formulation committee and the research scholars who helped in preparing this guideline.

I extend my sincere thanks to the entire faculty for the completion of this document on the thesis format guidelines
Syed Kashif Ahsan
Name of the Candidate

List of Abbreviations
AUB Abnormal Uterine Bleeding
CI Confidence interval
COC Combined Oral Contraceptives
DUB Dysfunctional Uterine Bleeding
EL Evidence level (level of evidence)
FSH Follicle Stimulating Hormone
GDG Guideline Development Group
GPP Good practice point
HMB Heavy Menstrual Bleeding
LH Luteinising Hormone
MBL Menstrual Blood Loss
MEA Microwave Endometrial Ablation
NCC-WCH National Collaborating Centre for Women’s and
Children’s Health
NHS National Health Service
NICE National Institute for Health and Clinical Excellence
OR Odds ratio
PBAC Pictorial Blood loss Assessment Chart
PPIP Patient and Public Involvement ProgrammeQALYS Quality adjusted life years
QoL Quality of Life
RCT Randomised controlled trial
REA Rollerball Endometrial Ablation
RR Relative risk
SD Standard deviation
SIGN Scottish Intercollegiate Guidelines Network
TBEA Thermal Balloon Endometrial Ablation
TCRE Transcervical Resection of the Endometrium
vWD Von Willebrand’s Disease
WMD Weighted mean difference

TABLE OF CONTENTS
Chapter Title Page number
1 INTRODUCTION 16
2 REVIEW OF LITERATURE 24
3 MATERIALS AND METHODS 39
4 RESULTS AND DISCUSSION 77
5 SUMMARY 89
6 CONCLUSION 7 CONTRIBUTION TO KNOWLEDGE 88
8 SUGGESTION FOR FUTURE RESEARCH 89
11 LIST OF PUBLICATIONS BASED ON THE 91
THESIS Introduction
DUB is a symptom complex that includes any condition of abnormal uterine bleeding in the absence of pregnancy, neoplasm, infection or other intrauterine lesion. Such bleeding is most often the result of endocrinologic dysfunction that inhibits normal ovulation. 1 Dysfunctional uterine bleeding is best defined as abnormal bleeding from the uterus in the absence of organic disease of the genital tract. The term DUB applies to any abnormal uterine bleeding, including disturbances of the menstrual cycle, regular or irregular uterine bleeding and alterations in amount and the duration of menstrual loss, but most commonly implies to excessive regular menstrual bleeding or essential menorrhagia. DUB is not one condition with one etiology, but is a group of disorders characterized by the dysfunction of the uterus, ovary, pituitary, hypothalamus or other part of reproductive system which results in abnormal or excessive uterine bleeding. In clinical practice the precise nature of the dysfunction is often not determined and the diagnosis of DUB is usually made by exclusion of organic disease of the genital tract. 2 The International Federation of Gynaecology and Obstetrics in November 2010, accepted a new classification system for causes of AUB in the reproductive years. The system based on the acronym PALM COEIN (polyps, adenomyosis, leiomyoma, malignancy and hyperplasia-coagulopathy, ovulatory disorders, endometrial causes, iatrogenic, not classified) was developed in response to concerns about the design and interpretation of basic science and clinical investigation that relates to the problem of AUB. 3 Dysfunctional uterine bleeding is one of the most common and significant gynaecological complaints and is seen in about 10-15% of women attending the gynaecological clinic.

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
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 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 thyroid 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.

Lacunae in the existing literature
Thyroid dysfunction is associated with a range of menstrual abnormalities, including oligomenorrhea, amenorrhea, and menorrhagia. Women with hypothyroidism may also be at increased risk of pregnancy loss. The connection between thyroid hormone levels and the menstrual cycle is mainly mediated by thyrotropin-releasing hormone (TRH), which has a direct effect on the ovary. Additionally, abnormal thyroid function can alter levels of sex hormone-binding globulin, prolactin, and gonadotropin-releasing hormone, contributing to menstrual dysfunction. For example, increased levels of TRH may raise prolactin levels, contributing to the amenorrhea associated with hypothyroidism.
Abnormality of menstruation is primarily a disorder of hypothalamico-pituitary-ovarian axis either through direct effect or indirectly by their effect on target organ. Endocrinological disturbances other than the reproductive hormones form a small but significant sub-group in the aetiopathogenesis of abnormal uterine bleeding. Amongst the endocrinological causes, after the pituitary, thyroid is probably the most important endocrine organ which exerts a broad range of effects on the development, growth, metabolism and function of virtually every organ system in the human body.7 Alterations in production and activity of the thyroid hormones thyroxine (T4) and tri-iodothyronine (T3) may result in menstrual abnormality. Both hyperthyroidism and hypothyroidism may result in menstrual disturbances. In hyperthyroidism, amenorrhoea was described as early as 1840 by Von Basedow. 8 The most common manifestation of hyperthyroidism is oligomenorrhoea and anovulation. It may also cause hypomenorrhoea or menorrhagia. Hypothyroidism even in subclinical form may result in excessive menstrual bleeding and severe blood loss. The mechanism of menorrhagia in hypothyroidism is incompletely understood. It is postulated that infrequent or absent ovulation leads to deficient secretion of luteinizing hormone which may result in relative estrogen excess thereby causing menorrhagia. There may be episodes of ammenorhoea interspersed with periods of heavy vaginal bleeding also. Various studies have reported that there are changes in cycle length, amount and duration of bleeding associated with thyroid disorders. Sometimes they may also present with infertility, recurrent pregnancy losses and galactorrhoea 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 possible in rapid and reliable manner. The diagnosis of various endocrine disorders can be easily made and medical treatment can be properly instituted. The results are usually very gratifying as patient is virtually symptom free on adequate treatment.

OBJECTIVE OF THE STUDY
Aims and objectives of our studies were as follows:-
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.

Evaluation of thyroid status (euthyroid, hypothyroid, or hyperthyroid) in dysfunctional uterine bleeding cases.

To observed the fraction of dysfunctional uterine bleeding cases having hypothyroid status.

HYPOTHESIS
Dysfunctional uterine bleeding (DUB), menstrual bleeding not explained by organic pathology in the pelvis or systemic deseases that exacerbate bleeding, is suspected when a reproductive-aged woman has excessive menstrual flow. Ovulatory DUB is most common in parous women aged 30-45 years. Cycles are regular and predictable and menstrual flows are preceded by breas soreness, mood or energy changes, or pelvic discomfort. Hypochronic microcytic anemia may result from the amount, rapidity, and duration of bleeding. Current evidence supports the hypothesis that DUB is associated with an increased total amount of prostaglandin in the uterus. Prostacyclin appears to be a likely cause of menorrhagia because it is locally produced within the intima of vessels and is a powerful vasodilator and effective inhibitor of platelet aggregation. DUB diagnosis requires careful exclusion of organic pathology through a detailed history, complete physical examination, and a complete blood count. A beta-human chorionic gonadotrophin measurement to rule out obstetric accident, curettage, hysteroscopy, biopsy, or laparoscopic visualization may be appropriate under different conditions. Curettage, thyroid hormone administration, ergot alkaloids, vitamin and mineral preparations, and iron therapy do little to correct the basic problem. Aspirin should be avoided in the week before and on the days of flow since in analgesic doses it inhibits the platelet thromboxanes that promote platelet agggregation and local vasoconstriction. Bed rest or reduced physical activity on days of flow is also advisable. Nonsteroidal antiinflammatory drugs are effective in reducing blood loss in women with DUB. The durgs are prostaglandin synthetase inhibitors, but the biochemical modifications causing an improved bleeding pattern are not well understood. All such drugs are effective, but some women experience greater relief with 1 formulation than another. Medroxyprogesterone acetate, 10 mg dialy for 7 days before the onset of flow, reduces bleeding in some women although the mechanism of action is unclear. Oral contraceptives (OCs) containing progestins derived from 19-nortestosterone inhibit endometrial proliferation, so ther is little tissue to be shed and little local prostaglandin to stimulate bleeding. Nonsmoking women under 40 years old with DUB who desire reversible contraception are excellent candidates for OCs. Aminocaproic acid is very expensive and has annoying gastrointestinal side effects. but is cost-effective for women with chronic anemia or life threatening uterine hemorrhage who wish to avoid hysterectomy. Danazol is of little usefulness because of its expense and side effects. Hysterectomy is an acceptable therapeutic option for many women.

Mental and physical complaints in thyroid disorders in the general population
To test the hypothesis that untreated overt and subclinical thyroid disorders and autoimmune thyroiditis (AIT) are associated with mental and physical complaints in the general population. A total of 3790 participants from the Study of Health in Pomerania (SHIP) with no known thyroid disorders were analyzed concerning their thyroid function (TSH, FT3, FT4), autoantibodies (TPO-Ab), their thyroid structure and size and their mental and physical complaints (Zerssen Complaint Scale). Overt hyperthyroidism (prevalence: 0.4%) was associated with a significantly lower total complaint-score than euthyroid subjects. Subjects with overt hypothyroidism (0.5%), subclinical hypothyroidism (0.7%), or subclinical hyperthyroidism (1.6%) were not different from controls in their total complaints. Females with AIT showed higher scores of tachycardia and anxiety independent from their thyroid function. In non-patient samples, hyperthyroidism is associated with positive effects on self-rated mental and physical health. AIT may be associated with negative effects on health also in euthyroid subjects.

Comorbid thyroid disease in patients with major depressive disorder – results from The European Group for the Study of Resistant Depression (GSRD)This multicenter study of the European Group for the Study of Resistant Depression (GSRD) aimed to explore the association between major depressive disorder (MDD) and comorbid thyroid disease. A total number of 1410 patients` characteristics in terms of demographic and clinical information were compared between MDD subjects with and without concurrent thyroid disease using descriptive statistics, analyses of covariance (ANCOVA) and binary logistic regression analyses. We determined a point prevalence rate for comorbid hypothyroidism of 13.2% and 1.6% for comorbid hyperthyroidism respectively. Patients with MDD+comorbid hypothyroidism were significantly older, more likely to be female, inpatient and suffering from other comorbid chronic somatic conditions. Furthermore, MADRS score at onset of the current depressive episode was significantly higher, psychotic features of depression were more likely pronounced. Overall, patients in the MDD+comorbid hypothyroidism group were rather treated with a combination of drugs, for example, pregabalin, antipsychotic drugs and mood stabilizers. In the MDD+comorbid hyperthyroidism group patients were significantly older, of Caucasian origin and diagnosed with other somatic comorbidities. In conclusion, our analyses suggest that abnormal thyroid function, especially hypothyroidism, is linked to depression severity and associated with distinct psychopathologic features of depression. However, comorbid thyroid disease has no influence on treatment response. A combination or augmentation of psychopharmacological drugs, especially with antipsychotics, mood stabilizers and pregabalin is more likely in patients with hypothyroid conditions. Thyroid disorder is frequently found in combination with other chronic somatic diseases including hypertension and heart disease.

Population studies have identified a positive correlation between subclinical hypothyroidism (SCH) and levels of total cholesterol and low-density lipoprotein (LDL) compared with those subjects whose TSH levels are within the normal reference interval. Almost all cases of suspected hypothyroidism will present to the general practitioner in the first instance. Whilst the classical signs and symptoms of both hyperthyroidism and hypothyroidism are well
known the features of early thyroid dysfunction are subtle. SCH is a common laboratory finding in general practice affecting up to one-fifth of women over 60 years of age;consequently, general practitioners have a low threshold for ordering thyroid function tests in adult patients. It remains contentious whether the discovery of a raised TSH level in general practice, with or without symptoms, is significant. This review aims to establish whether the null hypothesis is true: that there is no positive cardiovascular benefit in prescribing LT4 to patients with SCH.

REVIEW OF 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 metabolic 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 beautify 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
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, triiodothyronine 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 largest endocrine gland, is a brownish red, highly vascularised organ situated anteriorly 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.

Two main pairs of vessels contribute to the major arterial supply. The superior 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 laryngeal 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 separated 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.

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 thyroglobulin (also known as “organification of iodide”) to form 3:4 di-odotyrosine, 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 thyroxine 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-
Iodine – trapping/ Transport
Oxidation of iodides and organic iodination.

Coupling reaction of iodotyrosinsStorage and release of hormone

THE IODIDE CYCLE5607052165985

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.

½ in thyroidIn blood in form of
Inogranic iodides-0.5µgm – 1gm/IOB
Protein bound iodine
ThyroxineTri-iodithyronine?– globulin
Prealbumin5 – 8 gm/100 ml

THYROID HORMONES SYNTHESIS BY FOLLICLE EPITHELIAL CELL
1033145747395

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:
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.

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 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 synthesized 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.

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 ? and ?. ? subunits are similar in structure but ? 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 serum concentrations of T4and T3as well as other less well defined mechanisms.

REGULATION OF THYROID FUNCTIONS
914400318135
9144003810
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.

Hypothalamo-pituitary-thyroid complex.

Thyroid auto regulation.

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 ? – 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 ?-receptor activation. Catecholamines via ?2 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:
Calorigenic action
Stimulates oxygen consumption and heat production in all tissues. After thy-roidectomy, BMR is reduced by 40%.

Growth
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.

Metabolic actions
In physiological doses they are anabolic and stimulates protein syn-thesis but in high doses produce catabolism i.e. thyrotoxicosis.

They increase the glucose absorption from the gut, rate of its intracel-lular entry and its utilization. Large doses cause glycogenolysis.

They increase the rate of cholesterol synthesis in the liver, rate of its biliary excretion, its conversion to
bile acids, and faecal loss.

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.

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.

Gastrointestinal tract
Diarrhoea and constipation are commonly seen in hyper and hypothyroid-ism respectively. Achlorhydria is commonly associated with both.

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.

Haemopoetic systems
Incidence of megaloblastic anaemia is increased in hypothyroidism.

Skin Changes
Thyroxine deficiency causes deposition of muco-polysaccharides in connective tissues causing roughness of skin.

Miscellaneous
Creates wasteful creatinuriaVarious 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:-
Endogenous variables.

Pharmacological agents
Environmental alterations
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
228600217805
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 common reproductive system manifestation of hypothyroidism. Severe hypothyroidism may result into menorrhagia, intermenstrual bleeding or continued and severe blood loss.

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).

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 thyroxin in adequate dosage results into prompt alleviation of symptomatology.

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 galactorrhoea. Means (1948) noted menorrhagia in 32 per cent of 41 premenopausal patients 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 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), triiodothyronine (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 oestrogen. An increased rate of 16 -Alpha hydroxylation of estradiol in hypothyroidism results into increased formation of estriol. This altered oestrogen may result in abnormal feedback at the pituitary level with aberrant release of gonadotrophins resulting 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 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).

MATERIALS 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 AKU medical college and university,karachiSELECTION OF CASES
In our series both outdoor admitted patients were included. These patients were randomly divided into groups. These groups were
Menorrhagia
MenometrorrhagiaIntermenstrual spotting
PolymenorrhoeaThe patients suspected of organic gynecological 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.

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
Cervix:
Hypertrophy
Congestion
Discharge
Direction
Erosion
P/V:- 1.Uterus
Size – Normal
Bulky (more than normal but not 6 ; wks. enlarged multiparous size)
Consistency of uterus
Direction of uterus
Mobility of uterus
Tenderness of uterus
FornicesTender/NontenderAdnexa – 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
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).

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

ESTIMATION OF TOTAL THYROXINE LEVEL
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 conjugated 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 added 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 quantified.

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.

Stop Solution, 12 ml.

Materials required but not provided:
Precision pipettes: 40?l~200?l 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
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. A micro titer plate reader at 450nm wavelength was used in absorbance measurement.

Reagent preparation
All reagents were brought to room temperature (18 – 22°C) before use.

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.

Assay procedures
Desired number of coated wells were secured in the Holder and data sheet was made with sample identification.

50 ?l of standard, specimens, and controls were dispensed into appropriate wells.

100?l of Enzyme Conjugate Reagent was dispense into each well.

Thoroughly mixed for 10 seconds.

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

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

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

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

100?l of TMB solution was dispensed into each well and Gently mixed for 5 seconds.

Incubated at room temperature for 20 minutes without shaking.

By adding 100?l of Stop Solution to each well the reaction was stopped.

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

Calculation of results
The average absorbance values (A450) for each set of reference standards, control, and samples were calculated.

A standard curve was constructed by plotting the mean absorbance obtained for each reference standard against its concentration in ?g/dl on li-near graph paper, with absorbance on the vertical (y) axis and concentration on the horizontal (x) axis.

Using the mean absorbance value for each sample, the corresponding concentration of T4 in ?g/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 (?g/dl) Absorbance (450nm)
0 3.217
1 2.465
2.5 1.961
5 1.331
15 0.746
30 0.436

REFERENCE RANGE AND SENSITIVITY
Normal range was 5.0 to 13.0 ?g/dl. The minimum detectable concentration of thyroxin by this assay was 0.4?g/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 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.

Reagets1. 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 ?IU/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 ?l, 100 ?l and 1000 ?l.

3. Shaker for microtiterplates.

4. Stopping Solution: 12 ml 2N H2SO4.

Assay procedure
General remarks
All reagents and specimens were allowed to come to room temperature before the test was started.

All steps were completed without interruption.

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

All specimens and standards were running in duplicate concurrently so that all conditions of testing were the same.

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 ?l of standards or serum was dispensed to the appropriate wells.

3. 100 ?l 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 ?l 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 ?l of stopping solution
(2N H2SO4) to each well.

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?IU/ml by this method.

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.

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

ADEQUATE INCREASED
DURATION OF MENSTRUAL FLOW
0
1
2
3
4
5
6
7
8
9
10
A GROUPSB
C
D
DAYS
0
1
2
3
4
5
6
7
8
9
10
A GROUPSB
C
D
DAYS

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).

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 : 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 subjects. However, the duration of cycle was not significantly altered.
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)
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)

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).

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).

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
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
Table12: shows thyroid functions among patients of Group A. One pa- tients out of 20 was having thyroid functions suggestive of primary hypothyroidism 5% of total (TSH value 24.0 I ? U/ml, T4 -3.6 ? g/dl .

Group
A
(n =20) 48260384175T4
( 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

TABLE 13 : Thyroid functions in group B
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.

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

group were euthyroid . .

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

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
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.

RESULTS AND DISCUSSION
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-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-
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.

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 Serum thyroxine and TSH were within a normal limits.

TABLE 1A: Comparison of thyroid functions among group A, B, C and D
Group SerumThyroxine ( g/dl) Serum thyroid stimulating 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 comparisonp > 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%.

SERUM THYROXINE AND TSH IN VARIOUS GROUPS
SERUM THYROXINE SERUM T4
0
1
2
3
4
5
6
7
8
9
10
A
GROUPS
B
C
D
0
1
2
3
4
5
6
7
8
9
10
A
GROUPS
B
C
D

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
2A: Comparison of serum T4 and TSH in present study to thyroid hormone profile in study by Mukherji et al (1984)

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 patients 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.

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
TABLE 3A: Comparison of thyroid hormones profile in present study with that of study by Wilansky (1989)
Wilansky and Griesman (1989) studied 67% apparently euthyroid me- norrhagic women by a thyrotropin releasing hormone test. The baseline serum 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 carried 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-?- hydroxylation 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. Estimation of serum thyroid microsomal antibody and anti thyroglobulin antibody is required to confirm it.
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 nonavailability 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%
0
2
4
6
8
10
12
14
D
;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
2
4
6
8
10
12
14
D
;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

FREQUENCY OF HYPOTHYROIDISM IN GROUPS (A,B,C;D) ACCORDING TO CURRENT TSH RANGE
HYPOTHYROIDISM %
0
1
2
3
4
5
6
7
A
GROUPS
B
C
D
0
1
2
3
4
5
6
7
A
GROUPS
B
C
D

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 this3431969146066500 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 lateron.

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 status 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.

SUMMARY ; CONCLUSION

The present study was carried out in 50 patients selected from OPD/IPD Post Graduate Department of Medicine Agha khan university hospital.

The patients were categorized in four groups depending on the type of menstrual irregularity.
Group A (n=20) : Patients with menorrhagia.
Group B (n=15): Patients with menometrorrhagia.
Group C (n=10): Patients with polymenorrhoea.
Group D (n=5): Patients with intermenstrual spotting.
All these patients were clinically evaluated in detail for any gynecological or clinically 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 patients 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.
1646555364490003234055364490004336415364490004919980745490002454275112522000Mean 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).
5470525-165100049599853651250016478253651250032435803651250012941301125220004206875112522000The 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).
All the patients in group C (polymenorrhea) and Group D (Intermenstrual 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).

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%.
All the patients of polymenorrhea and intermenstrual spotting were euthyroid.
There was no evidence of hyperthyroidism in our study population.
13106401309370003769360245237000The diagnosis of thyroid dysfunction as a etiological factor in a small portion of cases of various menstrual irregularities gives a new direction to the medical management and it is well known that these patients respond dramatically 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 majority 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.

CONTRIBUTION TO KNOWLEDGE
The present study was carried out to find out the different patterns of menstrual abnormalities associated with thyroid disorders and to determine the type of AUB pattern in relation to the different thyroid disorders. A hospital-based prospective observational study was carried out in the department of Obstetrics and Gynaecology, AKU Medical College and Hospital, karachi, during the period from 1st June 2014 to 31st May 2015. 100 females who presented with AUB and were found to have thyroid dysfunction were recruited in this study. Exclusion criteria were given, e.g. pregnancy, IUCD, cervical or uterine malignancy, fibromyoma, polyp, etc. It was found that maximum number of patients was in the age group of 31-40 years (37%). Menorrhagia (42%) was found to be the commonest presenting abnormal uterine bleeding pattern. Majority (71%) were hypothyroids. 53.5% cases of hypothyroids had menorrhagia and 58.6% cases of hyperthyroids had oligomenorrhoea, making menorrhagia and oligomenorrhoea to be the commonest bleeding pattern in hypothyroidism and hyperthyroidism respectively. Thus, the study concludes that biochemical evaluation of thyroid function should be made mandatory in all cases of AUB.

SUGGESTION FOR FUTURE RESEARCH
The objective of the study was to evaluate the prevalence of thyroid dysfunction in dysfunctional uterine bleeding and to assess the menstrual and endometrial pattern in women with thyroid disorders. The present study was conducted on 200 patients who presented with dysfunctional uterine bleeding in gynecology OPD.. A woman with hypothyroidism, commonly presents with anovulation and unopposed oestrogen activity causes endometrial hyperplasia which may outgrow the blood supply and may cause local areas of necrosis and breakdown and produces bleeding. The menstrual irregularities are significantly more frequent in patients with thyroid dysfunction and menorrhagia was the commonest menstrual abnormality. The study concludes that biochemical evaluation of thyroid function should be made mandatory in all cases of abnormal uterine bleeding and this would avoid unnecessary surgeries and exposure to hormones.

Managing Thyroid Disease During Pregnancy, New ATA Guidelines
The 2017 guidelines, issued after 6 years of new evidence and experience, offer more targeted recommendations for clinical management of women who have thyroid disease once they become pregnant as well as postpartum. Four key changes in the new guidelines are highlighted.

Managing Hypoparathyroidism to Assure Optimal Clinical Care
American Thyroid Association Statement offers recommendations for clinical management of hypoparathyroidism following thyroid surgery.Following bilateral thyroid surgery, strategies to prevent the development of and minimize the risk for hypoparathyroidism (HypoPT), the most common post-surgical complication remains a critical diagnostic necessity.1 As such, endocrinologists and primary care practitioners (PCPs), who will be managing these patients, both before and after the surgery, have important roles to play in providing optimal care.

Influence of thyroid gland in women with abnormal uterine bleeding in reproductive age group as there is high incidence of thyroid diseases in our area, women with abnormal uterine bleeding are to be screened. This would also avoid unnecessary hormonal treatment and surgery in these patients. Further studies with more number of patients are required to evaluate the role of targeted screening at regular intervals for women with history of obstetric complications and infertility who have more risk of developing thyroid dysfunction
As there is high incidence of thyroid diseases in our area, women with abnormal uterine bleeding are to be screened. This would also avoid unnecessary hormonal treatment and surgery in these patients. Further studies with more number of patients are required to evaluate the role of targeted screening at regular intervals for women with history of obstetric complications and infertility who have more risk of developing thyroid dysfunction.
Thyroid Disorders in Women with PCOS have Increased Risk of Developing Hashimoto’s ThyroiditisHashimoto’s disease (autoimmune thyroiditis) worsens reproductive and metabolic outcomes in patients with polycystic ovary syndrome.

Researchers from Germany introduced evidence suggesting a threefold increase in the prevalence of Hashimoto’s thyroiditis in women with polycystic ovary syndrome (PCOS) as compared to rates of this condition in the general population. Although other investigators have reported similar results, this study comprises “the largest single cohort examined to date,
Polycystic ovarian syndrome is a heterogeneous endocrine disorder affecting approximately 6 to 8% of reproductive-age women. Nearly half of patients with a diagnosis of polycystic ovary syndrome experience infertility, and up to one-third have obesity Reproductive, metabolic, and physiological problems (such as those involving hair and skin) are frequent complaints in women with PCOS.

Since the presence of Hashimoto’s disease may exert negative effects on reproductive and metabolic parameters in women with PCOS, a better understanding of the impact of these comorbidities on these patients was warranted, according to the researchers.

As there is high incidence of thyroid diseases in our area, women with abnormal uterine bleeding are to be screened. This would also avoid unnecessary hormonal treatment and surgery in these patients. Further studies with more number of patients are required to evaluate the role of targeted screening at regular intervals for women with history of obstetric complications and infertility who have more risk of developing thyroid dysfunction.

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