“A STUDY ON ROLE OF THYROID DYSFUNCTION AND THYROID AUTOIMMUNITY IN INFERTILE WOMEN - A
CASE CONTROL STUDY”
A Dissertation submitted to
THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY CHENNAI
In partial fulfillment for the Degree of M.S., OBSTETRICS & GYNAECOLOGY
BRANCH – II
GOVERNMENT STANLEY MEDICAL COLLEGE CHENNAI
MAY 2020
CERTIFICATE BY THE INSTITUTION
This is to certify that the dissertation entitled “A STUDY ON ROLE OF THYROID DYSFUNCTION AND THYROID AUTOIMMUNITY IN INFERTILE WOMEN – A CASE CONTROL STUDY”is a bonafide work done by Dr. J. RAMEES FATHIMA at Government R.S.R.M Lying in Hospital, Stanley Medical College, Chennai-1. This dissertation is submitted to the Tamil Nadu Dr. M.G.R Medical University, Chennai in partial fulfillment of the university rules and regulations for the award of the M.S., Degree in Obstetrics & Gynaecology.
Prof. Dr. R. SHANTHI MALAR M.D., D.A., Dean,
Government Stanley Medical College, Chennai – 1
Prof. Dr. K. KALAIVANI M.D., DGO., DNB., Professor & HOD, Department of Obstetrics & Gynaecology, Government RSRM Lying in Hospital,
Stanley Medical College, Chennai.
CERTIFICATE BY THE GUIDE
This is to certify that this dissertation entitled “A STUDY ON ROLE OF THYROID DYSFUNCTION AND THYROID AUTOIMMUNITY IN INFERTILE WOMEN – A CASE CONTROL STUDY” submitted by Dr. J. RAMEES FATHIMA, appearing for Part II M.S., Obstetrics &
Gynaecology (Branch II) Degree Examination in May 2020, is a bonafide record of work done by her, under my direct guidance and supervision as per the rules and regulations of the Tamil Nadu Dr. M.G.R Medical University, Chennai.
I forward this dissertation to the Tamil Nadu Dr. M.G.R Medical University, Chennai, Tamil Nadu, India.
Prof. Dr. K. KALAIVANI M.D., DGO., DNB., Professor & HOD, Department of Obstetrics & Gynaecology, Government R.S.R.M Lying in Hospital,
Stanley Medical College, Chennai
DECLARATION BY THE CANDIDATE
I, Dr. J. RAMEES FATHIMA, solemnly declare that the dissertation entitled, “A STUDY ON ROLE OF THYROID DYSFUNCTION AND THYROID AUTOIMMUNITY IN INFERTILE WOMEN – A CASE CONTROL STUDY” is a bonafide work done by me at Government R.S.R.M Lying in Hospital, Stanley Medical College, Chennai, during June 2019 to October 2019 under the guidance and supervision of Prof. Dr. K.
KALAIVANI M.D., DGO., DNB., Professor & Head, Department of Obstetrics & Gynaecology. This dissertation is submitted to the Tamil Nadu Dr. M.G.R Medical University, Chennai, in partial fulfillment of requirement for the degree of M.S., Obstetrics & Gynaecology.
Place:
Date:
Dr. J. RAMEES FATHIMA Post graduate Department of Obstetrics & Gynaecology Government R.S.R.M Lying in Hospital, Stanley Medical College, Chennai.
ACKNOLEDGEMENT
I am grateful to Prof. Dr. R. SHANTHI MALAR M.D., D.A., Dean, Government Stanley Medical College, Chennai for granting me permission to undertake this study.
I take this opportunity to express my sincere and humble gratitude to Dr. K. KALAIVANI, M.D., D.G.O., DNB., Professor & Head of Department, Department of Obstetrics & Gynaecology, Govt. R.S.R.M.
Lying in Hospital, Chennai who not only gave me the opportunity and necessary facilities to carry out this work but also gave me encouragement and invaluable guidance to complete the task I had undertaken.
I am deeply indebted to my Assistant Professor Dr. G. PREETHA M.S., DGO., the mover behind this study for her able guidance and inspiration and constant support without which this would not have been possible.
I am very grateful to Prof. Dr. ANANTHI M.D., D.G.O. and RMO Dr. H. ANITHA VIRGIN KUMARI M.D., D.G.O., for their invaluable advice, constant guidance and supervision during this study.
I am extremely grateful to all our Professors and Assistant Professors, for their advice and support during this study. I sincerely thank my fellow postgraduates and friends for their support and cooperation.
I owe a great many thanks to all my patients without whom this study would not have been possible.
Finally, I thank Lord Almighty, who gave me the will power and showered blessings to complete my dissertation work.
CONTENTS
S.NO TITLE PAGE
NO.
1. INTRODUCTION 1
2. AIMS AND OBJECTIVES 3
3. REVIEW OF LITERATURE 4
4. MATERIAL AND METHODS 70
5. OBSERVATION AND RESULTS 73
6. DISCUSSION 90
7. SUMMARY 95
8. CONCLUSION 97
9. BIBLIOGRAPHY 10. ANNEXURES
ABBREVIATIONS
PROFORMA, CONSENT FORM MASTER CHART
ETHICAL COMMITTEE APPROVAL FORM PLAGIARISM CERTIFICATE
1
INTRODUCTION
Infertility affects approximately 10-15% of couples worldwide.
Infertility means the apparent failure of a couple to conceive after one year of unprotected intercourse. Among the various causes for infertility, female cause of infertility accounts for about 35%, whereas male factors contribute to about 30%. A combination of both factors accounts for about 20% and 15% causes of infertility are idiopathic or Unexplained.1 Ovulatory dysfunction, fallopian tube pathologies and endometriosis are mainly responsible for female infertility.
In India, approximately 13-19 million couples are likely to be infertile as per data from Indian Council of Medical Research (ICMR).2 National Family Health Survey in our country reports that 3.8% of women (between 40 & 44 years of age) were childless.3
Thyroid hormones have profound effects on reproduction and pregnancy. Normal thyroid function is important for fertility as well as for a healthy pregnancy.4 Thyroid disease is more common in women than in men. Because most thyroid disease is autoimmune in nature, an increased susceptibility to autoimmune diseases, perhaps secondary to the female endocrine environment, could be a contributing factor.
2
Thyroid dysfunction is implicated in a broad spectrum of reproductive disorders. Both hypo as well as hyperthyroidism can affect female reproductive functions. Women may develop abnormal sexual development, menstrual irregularities and also infertility.5,6 Thyroid disease when undiagnosed & untreated can contribute to infertility as well as sub-fertility.
Infertile women have high prevalence of thyroid autoimmunity as compared to fertile women. Autoimmune thyroid disorders are characterized by the presence of anti-peroxidase (anti TPO) and anti-thyroglobulin antibodies. Anti-thyroid antibodies can occur in asymptomatic, euthyroid women who have never suffered from a thyroid disease.7
It is better to detect and treat thyroid disease in early stages. Subtle thyroid disease can be easily diagnosed by the recently available sensitive laboratory assays. As a key to early diagnosis we should have a high index of suspicion as well as to screen for abnormal thyroid function, especially in women of childbearing age.
Evaluation of thyroid status in the infertile women is not only important because it is significant and most common but also its treatment is very simple and often has reversible or preventable effects on infertility.8,9
3
AIMS AND OBJECTIVES
AIM OF THE STUDY:
To study the prevalence of abnormal thyroid function and thyroid autoimmunity in Infertile and Fertile women.
To correlate the thyroid dysfunction with the presence of anti-thyroid peroxidase antibodies.
OBJECTIVES OF THE STUDY:
To study the association between anti-thyroid peroxidase antibodies and infertility among women.
To determine the correlation between anti-thyroid peroxidase antibodies and T3, T4, TSH levels in females with infertility.
4
REVIEW OF LITERATURE
INFERTILITY:
By definition, infertility is the apparent failure of a couple to conceive after one year of unprotected regular intercourse. Worldwide the incidence of infertility varies between 5% to 15%. Nowadays, the term subfertility is used instead of infertility.
Figure 1: Global Prevalence of primary infertility among women who seek a child [2010].
Infertility can be subdivided into
Primary infertility: Conception has never occurred.
Secondary infertility: Failure to conceive after prior conception.
5
NORMAL REPRODUCTIVE EFFICIENCY:
Normal sperm can survive in the female reproductive tract and retain the ability to fertilize an egg for at least 3 and up to 5 days, but an oocyte can be successfully fertilized for only approximately 12 to 24 hours after it is released.10 Consequently, in virtually all conception cycles, intercourse occurs sometime within the 6-day interval ending on the day of ovulation.
Based on observation,80% of normal couples achieve conception within one year with adequate frequency (4 to 5 times a week). Timed coitus is commonly advised for infertile couples. Infertile couples should be educated about normal human reproductive efficiency
Time Required for Conception in Couples Who Will Attain Pregnancy11
Time of exposure % Pregnant
3 months 57%
6 months 72%
1 year 85%
2 years 93%
6
AGE & FERTILITY:
The optimal age for conception is 20-35 years in a woman. After the age of 40 years, the fertility rate is reduced. There is also an increased risk of chromosomal abnormalities or malformations in the fetus. Fertility in women peaks between the ages of 20 & 24. It decreases relatively between age 30 to 32, and then declines progressively.12, 13
Figure 2: Percentage distribution of Age and Fertility in women
7
Physiology of Reproductive Aging:
Follicular depletion: During fetal life, germ cells rapidly proliferate by mitosis to yield approximately 6-7 million oogonia by 16-20 weeks of pregnancy.14 After entering the first meiotic division and becoming oocytes, the number of germ cells falls to between 1 and 2 million at birth, and to about 300,000 by the onset of puberty. By age 40, the size of the follicular pool declines to approximately 25,000, and at menopause, less than 1,000 follicles remain.15
Genetics of Reproductive Aging:
The total number of follicles at birth, and the age when the supply is exhausted, are genetically determined.16 There is good correlation between menopausal age in mothers and daughters and between sisters, suggesting that genetic factors play an important role in determining menopausal age.17 Approximately 10% of women become menopausal by the age of 45, probably because they were endowed with a smaller than average ovarian follicular pool that is functionally depleted at an earlier age.18
The Aging Follicle and Oocyte:19 Fertility and the prevalence of euploid oocytes decrease progressively with age.
8
Aging and Male Fertility:
Modest age-related decreases in semen volume, sperm motility, and morphologically normal sperm, but not sperm density, have been observed.20 Possible biological mechanisms that might explain an age-related decline in male fertility include Sperm chromosomal abnormalities may increase in frequency with age and adversely affect early embryonic development.21 The testes and prostate also exhibit morphological changes with aging that might adversely affect both sperm production and the biochemical properties of semen.22
GUIDING PRINCIPLES IN THE EVALUATION OF INFERTILITY:
The evaluation of infertility should focus on the couple and not on one or the other partner. Joint visits also help to ensure that both partners understand any information, options, and recommendations that may be offered.
Basic goals for evaluation in infertile couples:
1) To identify & to correct specific causes of infertility, when possible.
2) To provide accurate information & to dispel the misinformation commonly gained from friends and mass media.
3) To provide emotional support during a trying time.
9
4) To guide those couples in whom standard forms of treatment do not achieve success to alternatives, such as ART, use of donor gametes (oocytes/sperm), and adoption.
It is customary to wait for at least one year of regular unprotected intercourse before investigating infertile couple, except in elderly couple and women with irregular menstrual cycle.
Conception is the result of successful fertilization of the female egg by the sperm. Hence the couple should be counselled individually and then together because both partners contribute varyingly to the occurrence of the infertile state. Male is directly responsible in about 30-40% of cases, Female is about 40-55% and both responsible in about 10% of cases. Counselling must be an ongoing process during both evaluation and treatment.
Lifestyle and environmental factors can indeed influence fertility in many ways. Lifestyle modifications for couples attempting to conceive include
Smoking cessation
Maintaining BMI between 20 & 25
Limiting alcohol consumption to 4 or fewer drinks per week and
Limiting caffeine intake to less than 250 mg/day
10
CAUSES OF INFERTILITY:
The causes of infertility can be grouped in to four categories:
(1) Male factor infertility (2) Female factor infertility (3) Combination of both
(4) Idiopathic or unknown infertility
The major causes of infertility include ovulatory dysfunction, fallopian tube & peritoneal pathologies and male factors.
Figure 3: Distribution of infertility causes in Infertile couples
35%
15%
35%
10% 5%
Couples
Male problems Ovulatory dysfunction Tubal & Pelvic pathology Unexplained infertility Unusual problems
11
Figure 4: Distribution of infertility causes in Infertile women
MALE FACTOR INFERTILITY Genetic factors:
Abnormal Y chromosome, XXY in Klinefelter syndrome Pre testicular – Hormonal disorders:
Hypothalamic disorder, Kallmann syndrome
Pituitary disorder
Hyperprolactinemia
Hypothyroidism
Adrenal gland disorder
Diabetes
40%
40%
10%
10%
Women
Ovulatory dysfunction Tubal & Pelvic pathology Unusual problems Unexplained infertility
12
Testicular disorders:
Varicocele
Orchitis (traumatic, mumps, TB, gonorrhoea)
Drugs, Radiation, Cryptorchidism Post-Testicular disorders:
Duct obstruction – congenital absence, inflammatory block, surgical trauma, Young syndrome
Infections with E.coli, staphylococci, chlamydia, mycoplasma.
Prostatitis, vesiculitis.
Disorders of sperms and vesicular fluid:
Sperm antibodies, Immotile cilia syndrome Sexual dysfunction:
Low coital frequencies
Impotence
Premature ejaculation, Retrograde ejaculation Psychological and environmental factors:
Smoking
Alcohol consumption
Tobacco chewing
Obesity, Chronic illness
13
FEMALE FACTOR INFERTILITY Ovarian Factor: Ovulatory Dysfunction
Polycystic ovarian syndrome
Hypogonadotrophic hypogonadism
Hypergonadotrophic hypogonadism
Cervical Factor: Abnormalities of Sperm-Mucus Interaction Uterine Factor: Anatomic and Functional Abnormalities
Congenital abnormalities
Fibroids
Treatment for cervical carcinoma
Asherman’s syndrome
Tubal Factor: Tubal Occlusion and Adnexal Adhesions
Pelvic inflammatory disease (chlamydia, gonorrhoea)
Endometriosis
Previous sterilisation
Previous pelvic or abdominal surgery Peritoneal factor:
Adhesions due to previous abdominal surgeries, Endometriosis
14
Hormonal causes:
Pituitary dysfunction
Hypothalamic disorder
Hyperprolactinemia
Thyroid dysfunction Dyspareunia and vaginal causes Congenital defects in genital tract Infection in the lower genital tract
The infertility evaluation is designed to isolate and test the integrity of each component and to identify any abnormalities that might impair or prevent conception. The pace and extent of evaluation should be based on the couple's age, duration of infertility, medical history, physical examination, and preferences.
INDICATIONS FOR EVALUATION:
Evaluation should be offered to all couples who have failed to conceive even after a year of unprotected regular intercourse. But a year of infertility is not a prerequisite for evaluation.
15
Regardless of age or duration of infertility, immediate evaluation should be offered to: 23
Women with irregular or infrequent menses,
Women with a history of pelvic infection or endometriosis, and
Women having a male partner with known or suspected poor semen quality
Women over 35 years of age after 6 months of unsuccessful effort Education should be offered to all infertile couple. It is always helpful to explain the reproductive process, to inform couples that normal cycle fecundability is approximately 20%, and to discuss the relationship between age and fertility.
PRELIMINARY EVALUATION OF THE INFERTILE COUPLE:
Evaluation of infertile couple should begin with a detailed history as well as physical examination of both partners. This often helps to find a specific cause for infertility and also for the evaluation of responsible factors. In infertile women, the following medical history and physical examination can be done.24
16
History:
Gravidity, Parity, pregnancy outcomes and its complications if any.
Menstrual cycle length & its difficulties.
History of any PID, sexually transmitted infections.
Symptoms of suggestive of thyroid disease and other hormonal abnormalities
Occupation, Use of tobacco, alcohol, and other drugs
Family history of early menopause, reproductive failure
Duration of infertility, Frequency & timing of coitus.
Any past surgeries and past medical illnesses like diabetes
Current medicines and any allergies.
Physical Examination:
Weight and BMI.
Enlargement of thyroid gland.
Breast secretions and their character, signs of androgen excess
Pelvic or abdominal tenderness,
Any organ enlargement or mass lesion
Vaginal or cervical abnormality, its secretions, any discharge.
Cul-de-sac or adnexal mass, tenderness and nodularity.
17
Baseline investigations:
Complete blood count (CBC), Blood sugar
VDRL, HIV, HBsAg testing
Mantoux test, Chest X-ray, Transabdominal USG
EVALUATION OF MALE FACTOR INFERTILITY:
(1) Semen Analysis
The initial evaluation for male factor infertility should include at least one properly performed semen analysis.25 An abnormal semen analysis always reveals a male infertility factor.
WHO Normal reference values:26
18
Specialized tests:
Sperm Autoantibodies, Acrosome reaction
Sperm Penetration Assay, Human Zona Binding Assay
Computer Assisted Sperm Analysis (CASA)
Measuring sperm creatine phosphokinase & reactive oxygen species.
Sperm Chromatin Structure and DNA (2) Endocrine evaluation:
Indications for endocrine evaluation in infertile men include27
An abnormal semen analysis (particularly a sperm concentration less than 10 million/ml)
Sexual dysfunction (decreased libido, impotence), and
Clinical symptoms or findings that suggest a specific endocrinopathy.
Following hormonal analysis can be done: Serum FSH, LH, Serum Testosterone, Serum estradiol, Serum Prolactin, Thyroid profile
(3) Urological evaluation:
Palpation of the spermatic cord may reveal a varicocele28
Digital rectal examination defines the size and symmetry of prostate.
Transrectal ultrasonography, Transscrotal ultrasonography
Renal ultrasonography, Testis biopsy
19
(4) Chromosomal analysis
Chromosomal anomalies resulting in testicular dysfunction (Klinefelter syndrome; 47, XXY)
Y chromosome microdeletions associated with abnormalities of spermatogenesis.29
TREATMENT OF MALE FACTOR INFERTILITY:
Education: Sexual counselling – coital frequency, timing & position
Substance abuse: Avoidance of tobacco (smoking, chewing), Moderate alcohol consumption, Avoidance of drug abuse
Correct Endocrinopathies: Treatment of diabetes and thyroid disorders
Reduce heat around the scrotum: Avoid hot baths, wear loose cotton underwear, avoid strenuous activities and working in hot environment
Antibiotics: to treat epididymo-orchitis, prostatitis and STDs
Surgical treatment: Surgical correction of varicocele & undescended testes in childhood, Micro surgical vaso-vasal or vaso-epididymal anastomosis for obstruction of vas, Vasovasostomy for reversal of vasectomy operation
For oxidative stress: Antioxidants like Vitamin E, Vitamin C, Lycopene, N-acetyl cysteine, Carnitine, Selenium, Pentoxifylline.
20
Premature ejaculation: Selective serotonin reuptake inhibitors (dapoxetine)
Hormone therapy:
Testosterone, pituitary hormones, GnRH for spermatogenesis.
Bromocriptine for hyperprolactinemia
Erectile dysfunction treatment:
Phosphodiesterase 5 inhibitor –Sildenafil, Tadalafil
Intracavernosal injection therapy, Vacuum constriction devices
Intraurethral prostaglandin suppositories, Penile prosthesis.
Artificial insemination indicated in
Oligospermia impotency – ejaculatory failure, Hypospadias
Antispermal antibodies, Premature/Retrograde ejaculation
Unexplained infertility
HIV positive male or female, Chronic medical disorder
Other treatment methods:
In Vitro Fertilization
Gamete Intrafallopian transfer (GIFT) technique
Microassisted fertilization (MAF) technique
Microsurgical epididymal sperm aspiration (MESA)
Percutaneous epididymal sperm aspiration (PESA)
21
EVALUATION OF FEMALE FACTOR INFERTILITY:
(1) Ovarian Factor: Ovulatory Dysfunction
The evaluation of ovulation is a core component of the evaluation for infertility. Disorders of ovulation account for approximately 20% of the problems identified in infertile couples.
Menstrual history:
Menstrual history is significant to establish a diagnosis of anovulation.
Women with irregular or infrequent menses may ovulate, but not consistently. They do not require specific diagnostic tests to prove what is already obvious.
Basal Body Temperature (BBT):
As a test of ovulation, daily BBT recordings are based on the thermogenic properties of progesterone, as levels rise after ovulation, BBT also increases. Coital timing can be optimized by suggesting intercourse on alternate days beginning 7 days before the earliest observed rise in BBT and ending on the latest day it has been observed.
22
Serum Progesterone Concentration:
Serum progesterone measurement is the simplest and reliable test of ovulatory function. A progesterone concentration less than 3 ng/mL implies anovulation, except when drawn immediately after ovulation or just before the onset of menses, when lower levels naturally might be expected.30 Serum progesterone level should be done one week before the expected onset of menses (21st day in a 28-day cycle). Normal value should be more than 20ng/mL. Serum progesterone levels also have been used to evaluate the quality of luteal function.
Urinary LH Excretion:
“Ovulation prediction kits” or “LH kits” are designed to detect the mid-cycle LH surge in urine. Ovulation generally occurs 14-26 hours after detection of the LH surge and almost always within 48 hours.31 The interval of greatest fertility includes the day the surge is detected and the following 2 days.
Endometrial Biopsy and Luteal Phase deficiency:32
Endometrial biopsy can be used as a test of ovulation. It is based on the characteristic histologic changes induced by progesterone. During the follicular phase of the cycle, the endometrium exhibits a proliferative
23
pattern. During the luteal phase, Progesterone secreted by the corpus luteum induces the “secretory” transformation of the endometrium. In the absence of treatment with exogenous progesterone or a synthetic progestin, a secretory endometrium implies recent ovulation. Until recently, endometrial biopsy for diagnosis of luteal phase deficiency was considered a basic element of the infertility evaluation.
Transvaginal Ultrasonography: (TVUS)
TVUS permits direct observation of events in the ovary just before and immediately after ovum release.33 Serial TVUS provides detailed information about the size and number of pre-ovulatory follicles and the most accurate estimate of when ovulation occurs.
Figure 5: Transvaginal Ultrasonography
24
TESTS FOR OVARIAN RESERVE
Serum FSH (Follicle stimulating hormone) on day 3 >15mIU/mL
Serum AMH (Anti Mullerian hormone) <8.1 pmol/L
Serum Inhibin <400 pg/mL
Transvaginal ultrasound:
Antral follicle count (AFC) >10 follicles of 2-10mm diameter
Mean ovarian volume >3mL
Clomiphene citrate challenge test:
100mg Clomiphene from day 5 to 9
FSH on day 3 and 10 (<10mIU/mL)
Estradiol on day 3 (<80 pg/mL)
Infertile women with ovulatory dysfunction are obvious candidates for ovulation induction. In the majority of cases, it is reasonable and appropriate to begin treatment immediately, even before other potential causes of infertility have been investigated. If anovulation is the only obstacle to overcome, most couples will conceive promptly without further interventions.
25
(2) Cervical Factor: Abnormalities of Sperm-Mucus Interaction
Estrogen stimulates cervical mucus production, and mucus becomes more abundant and watery, less cellular, and more easily penetrated by sperm.34 Progesterone inhibits cervical mucus production and renders it opaque, viscid, and impenetrable. Cervical mucus specimen should be evaluated for pH, clarity, cellularity, viscosity, salinity and for the number &
motility of surviving sperm.
SPINNBARKEIT TEST is used for testing viscosity of mucus and indicates the length to which a column of mucus can be stretched in centimeters. FERN TEST: It means the complexity of the network of crystals that forms when mucus is dried on a glass slide. It is used for salinity of mucus.
The presence of motile sperm confirmed effective coital technique and sperm survival and the number of sperm (per high power field) was used to predict semen quality (sperm density and motility) and cycle fecundability.
Most considered even a single motile sperm in most fields a “positive” or normal test result. The postcoital test for diagnosis of cervical factor is no longer recommended.35
26
(3) Uterine Factor: Anatomic and Functional Abnormalities
The anatomic uterine abnormalities that can adversely affect fertility include
Congenital malformations
Leiomyomas
Intrauterine adhesions
Endometrial polyps
The only functional uterine abnormality of specific interest in the evaluation of infertility is chronic endometritis.
There are three basic methods for evaluation of the uterine cavity:
(1) Hysterosalpingography,
(2) Transvaginal ultrasonography or Saline sonohysterography (3) Hysteroscopy
Hysterosalpingography:
Hysterosalpingography (HSG) accurately defines the size and shape of the uterine cavity
It provides clear images of uterine developmental anomalies like unicornuate, septate, bicornuate, and didelphys uterus. It can also identify submucous myomas and intrauterine adhesions.
27
Figure 6: Hysterosalpingography (HSG)
Transvaginal Ultrasonography and Saline Sonohysterography:
Transvaginal ultrasonography (TVUS) can be used for evaluation of uterine factors in infertile women.
Saline sonohysterography, involving TVUS during or after introduction of sterile saline through a catheter, crisply defines cavity contours and demonstrates even small intrauterine lesions.36
28
Hysteroscopy:
Hysteroscopy is the gold standard method for both diagnosis and treatment of intrauterine pathology that may adversely affect fertility.
Figure 7: Hysteroscopy
29
Hysteroscopy can be used in the diagnosis and management of infertile women with
Congenital Uterine Anomalies
Uterine Myomas, Endometrial Polyps
Intrauterine Adhesions (Asherman’s Syndrome)
(4) Tubal Factor: Tubal Occlusion and Adnexal Adhesions
Tubal and peritoneal pathology is among the most common causes of infertility. It is the primary diagnosis in approximately 30-35% of both younger and older infertile women.37 History of any tubal surgery, pelvic inflammatory disease, septic abortion, or ectopic pregnancy indicates the possibility of tubal damage. PID is the major cause of tubal factor infertility and ectopic pregnancies. Tubal obstructions can be classified in to:
Proximal tubal obstruction
Distal tubal obstruction
Mild (fimbrial agglutination)
Moderate (fimbrialphimosis)
Severe (complete obstruction with hydrosalpinges)
30
Figure 8: Tubal factor infertility
Methods for evaluation of tubal patency in infertile women:
Hysterosalpingography, Sonohysterosalpingography
Laparoscopic chromotubation
Hysteroscopy, Falloscopy, Fertiloscopy, Ampullary &
Fimbrialsalpingoscopy
Figure 9: Salpingoscope
31
Hysterosalpingography (HSG):
HSG is best scheduled during the 2-5 day interval immediately following the end of menses. (usually 9th or 10th day of the cycle) This is to minimize risk for infection, avoid interference from intrauterine blood &
clot, and to prevent any possibility that the procedure might be performed after conception.
EVALUATION OF UNEXPLAINED INFERTILITY:
The incidence of unexplained infertility contributes to about 10% among infertile populations.38 Normal semen quality, normal ovulatory function, a normal uterus, and bilateral tubal patency points to the diagnosis of unexplained infertility. Much of unexplained infertility relates to the natural decline in fertility with increasing age. Unexplained infertility is more common in women over age 35.39
Logically, the most likely occult causes of infertility relate to abnormalities in gametes or implantation. All of the potential causes of unexplained infertility could co-exist with known causes for infertility. The likelihood of pregnancy without treatment decreases progressively with increasing age of the female partner and increasing duration of infertility.40
32
TREATMENT OF FEMALE INFERTILITY:
After the work-up, a proposal for treatment should be discussed with the couple, with informed consent, estimated prognosis and counselling.
Primary approaches include
Ovulation induction for women with ovulatory dysfunction;
Endoscopic or surgical procedures to alleviate tubal obstruction;
Ablation of endometriosis; and
Intrauterine insemination (IUI) with donor or partner sperm.
When all of these approaches fail, Assisted Reproductive Technology (ART) is the ultimate tool. ART comprises
1) In vitro fertilization (IVF) and
2) Intracytoplasmic sperm injection (ICSI)
Indications for IVF Indications for ICSI 41, 42
Tubal damage
Bilateral salpingectomy
Endometriosis
Mild male infertility
Idiopathic infertility
Sperm abnormalities
Failure of IVF
Ejaculatory disorders
Preimplantation diagnosis
33
TREATMENT OF OVULATORY DYSFUNCTION:
INDUCTION OF OVULATION:
Modern ovulation induction strategies are highly effective. When a specific cause for anovulation can be identified, treatment often restores normal cycle fecundity.
Preliminary evaluation for all anovulatory women:
Screening for impaired glucose tolerance and diabetes
It is recommended for all obese anovulatory women with PCOS.
Up to 35% exhibit impaired glucose tolerance and 7-10% meet criteria for type 2 diabetes mellitus.43
Screening semen analysis
Preliminary HSG and transvaginal ultrasonography
The best initial treatment for obese anovulatory women is weight loss, when it can be achieved. Even modest weight loss (5-10% of body weight) often restores ovulatory cycles in obese anovulatory women with PCOS.
34
Clomiphene citrate:
Clomiphene is a non-steroidal triphenylethylene derivative that acts as a selective estrogen receptor modulator (SERM), having both estrogen agonist and antagonist properties.44 It is the drug of choice for ovulation induction in infertile women with Eugonadotropic Euestrogenic Anovulation (WHO Group II) and is ineffective in women with hypogonadotropic hypogonadism (WHO Group I)
Clomiphene is given orally, on the 3rd to 5thday after the onset of a spontaneous/induced menses. Dosage is to start with single 50 mg tablet daily for a 5-day interval. Most women who respond to clomiphene will respond to either 50 mg (52%) or 100 mg (22%) 45
Clomiphene will induce ovulation successfully in 70-80% of properly selected women.46 Cumulative pregnancy rates of 70-75% can be expected over six to nine cycles of treatment.47
Aromatase inhibitors:
Letrozole (2.5-7.5 mg daily) and Anastrazole (1 mg daily) administered for a 5-day interval in a manner very similar to that for clomiphene treatment. They have a lower risk for conceiving a multiple pregnancy.
35
Exogenous Gonadotropins:
Exogenous gonadotropins have been used to induce ovulation in gonadotropin-deficient women and those who fail to respond to other forms of treatment. The only exogenous gonadotropins available was human Menopausal Gonadotropins (hMG, menotropins). It is an extract prepared from the urine of postmenopausal women containing equivalent amounts (75 IU) of FSH & LH per ampule or vial. It is given as intramuscular injection.
Indications for Gonadotropin Treatment:
Hypogonadotropic Hypogonadism
Clomiphene-Resistant Anovulation
Unexplained Infertility
Pulsatile Gonadotropin-Releasing Hormone: (GnRH)
Exogenous GnRH is the drug of choice for treatment of anovulatory infertile women with hypogonadotropic hypogonadism. Exogenous GnRH is most effective when administered intravenously in low doses (2.5- 5.0 mg/pulse) at a constant interval (every 60-90 min).48
36
Dopamine Agonists:
Dopamine agonists are the treatment of choice for ovulatory dysfunction in hyperprolactinemic infertile women.
Bromocriptine (1.25-2.5 mg at bedtime), Cabergoline (0.25 mg twice weekly) can be used. Cabergoline has proven effective in 70-80% of hyperprolactinemic women who are resistant to or cannot tolerate bromocriptine treatment. Cyclic menses are restored in 70-90%, usually within 6-8 weeks after treatment begins.49, 50
Laparoscopic Ovarian Drilling:
Laparoscopic ovarian drilling can be an effective therapeutic option for clomiphene resistant anovulatory infertile women. This procedure is best reserved for women who are unable or unwilling to accept the costs &risks associated with gonadotropin therapy.
TREATMENT OF TUBAL FACTOR INFERTILITY:
For women with tubal factor infertility, treatment options include reconstructive surgery and in vitro fertilization.
37
Distal Tubal Obstruction:
In younger women with mild distal tubal occlusion, laparoscopic surgery is an alternative to IVF,
IVF is a better choice, when disease is severe or pregnancy does not occur during the first postoperative year.
For older women with any significant degree of distal tubal disease, IVF is generally the first and best option.51
Laparoscopic salpingectomy improves IVF pregnancy rates in women with hydrosalpinges.
Proximal Tubal Obstruction:
Microsurgical segmental tubal resection and anastomosis is a proven treatment for true proximal tubal obstruction.
Proximal tubal cannulation using hysteroscopic or fluoroscopic methods is a proven alternative to traditional microsurgical repair.
In vitro fertilization represents the best treatment option for bipolar tubal disease which involves both proximal and distal tubal obstruction.52
38
TREATMENT OF ENDOMETRIOSIS:
Endometriosis is defined by the presence of endometrial glands and stroma outside of the uterus. It is associated with both pelvic pain and infertility.
Medical treatment: Medical therapies are used for pain management in endometriosis. They include:
Estrogen-progestin contraceptives
Progestins
Gonadotropin-releasing hormone (GnRH) agonists
Aromatase inhibitors
Danazol
Medical therapy generally is not effective for the management of endometriomas larger than 1 cm.
Surgical treatment: For women having moderate or severe endometriosis, surgery is the treatment of choice. Apart from relieving pain, surgery may also improve fertility.
39
ASSISTED REPRODUCTIVE TECHNOLOGIES (ART)
Assisted reproductive technologies (ART) encompass all techniques involving direct manipulation of oocytes outside of the body. The most common form of ART is in vitro fertilization (IVF)
IVF involves a sequence of coordinated steps as follows:
(1) Controlled ovarian hyperstimulation (COH) with exogenous gonadotropins
(2) Retrieval of oocytes from the ovaries under the guidance of transvaginal ultrasonography
(3) Fertilization in the laboratory
(4) Transcervical transfer of embryos into the uterus INDICATIONS FOR IVF:
Tubal factor infertility
Endometriosis
Male factor infertility
Ovulatory dysfunction
Unexplained infertility
Ovarian failure & diminished ovarian reserve
40
TREATMENT OF UNEXPLAINED INFERTILITY:
As the cause of unexplained infertility is unknown, all treatments are empiric.
The most common treatments include (1) Intrauterine insemination (IUI)
(2) Ovarian stimulation with clomiphene / gonadotropins and IUI (3) In vitro fertilization (IVF)
Combined treatment with clomiphene and IUI is commonly recommended for couples with unexplained infertility. Treatment with gonadotropins and IUI is effective for couples with longer durations of unexplained infertility (>3years). Treatment with gonadotropins and IUI can be considered for couples who fail to conceive during treatment with clomiphene & IUI and when clomiphene treatment fails to stimulate multiple follicular development. Assisted Reproductive Technology – IVF is clearly the most effective treatment for couples with unexplained infertility, regardless whether it is the first or the last treatment.
To conclude, with proper evaluation and treatment, the majority of infertile couples will achieve pregnancy. For those who fail simpler specific treatments, ART and adoption are both realistic options.
41
INFERTILITY & THYROID
Thyroid hormones have profound effects on reproduction and pregnancy. Thyroid dysfunction is implicated in a broad spectrum of reproductive disorders. Both hypo as well as hyperthyroidism can affect female reproductive functions. Women may develop abnormal sexual development, menstrual irregularities and also infertility.5,6 Thyroid disease when undiagnosed & untreated can contribute to infertility as well as sub- fertility.
Thyroid dysfunction can affect fertility by causing anovulatory cycles, luteal phase defect, hyperprolactinemia and sex hormone imbalances. Hence normal thyroid function is necessary for fertility as well as for a healthy pregnancy.
Thyroid evaluation should be done in any woman
Who wants to get pregnant with family history of thyroid problem or
Irregular menstrual cycle or
Had more than two miscarriages or
Is unable to conceive after 1 year of unprotected intercourse
42
The prevalence of thyroid dysfunction in infertile women was found to be 33.3% in a study by Rahman et al.,53 and 23% by Sharma et al.,54
As thyroid hormones have significant and reversible effect on female fertility, so it is very important to assess thyroid status of an infertile female.55 Thyroid hormones measurement is considered an important step of infertility workup in women.56
THYROID GLAND:
Thyroid gland is one of the most important endocrine gland. It was described by Galen and was named “glandulae thyroidaeae” by Wharton in 1656. Hyperthyroidism was first described by Parry in 1825 followed by Graves and Basedow in 1835 and 1840 respectively. Hypothyroidism was first described by Gull in year 1874.57
Thyroid Anatomy & development:
Thyroid is a butterfly shaped endocrine gland located in front of the neck. The word thyroid is derived from Greek, thyreos, shield, plus eidos, form. Thyroid gland has two lobes connected by an isthmus. It is located anterior to the trachea between the cricoid cartilage & the suprasternal notch.
It weighs approximately about 12–20 g in size.
43
Figure 10: Anatomy of Thyroid Gland
Thyroid gland develops from the floor of the primitive pharynx during the third week of gestation. Medullary C cells develop from the ultimobranchial body which secretes the hormone, Calcitonin. Thyroid hormone synthesis normally begins at about 11 weeks of gestation.58
Thyroid Hormones:
The principal hormones of thyroid gland are the iodine-containing amino acid derivatives of thyronine.
Thyroxine (3,5,3’,5’-L-tetraiodothyronine) or T4
Triiodothyronine (3, 5, 3’-L-triiodothyronine) or T3
44
Thyroxine was isolated by Kendall in 1915. Harington in 1926 elucidated the structural formula of thyroxine. Triiodothyronine was isolated by Gross and Pitt-Rivers in 1952.58,59 T3 is four to five times more potent than T4. T4 is considered to be a prohormone without any intrinsic biological activity.60
Synthesis of Thyroid hormones: Stages include57,61
Iodine trapping and uptake of iodine by the Thyroid follicular cells
Organification (iodination)
Coupling reaction
Storage of thyroid hormones
Secretion of thyroid hormones
Transport of thyroid hormones:62
Thyroid hormones are transported in two forms, protein bound and free. The free hormones such as free T3 (FT3) and free T4 (FT4) are the physiologically active fraction. The bound hormone is metabolically inactive and are bound to thyroxine binding globulin (TBG), thyroxine binding pre albumin (TBPA) also called transthyretin and albumin.
45
Regulation of Thyroid hormone secretion:
Thyroid function is primarily regulated by variations in the circulating level of Thyroid stimulating hormone (TSH) from the Pituitary gland. TSH secretion is increased by thyrotropin-releasing hormone (TRH) from Hypothalamus. TSH is inhibited in a negative feedback fashion by circulating free T4 & T3. T4 & T3 feedback to inhibit hypothalamic production of TRH & TSH. TSH stimulates production of T4 & T3 hormones.63
Figure 12: Regulation of Thyroid hormone synthesis
46
Biological functions:57, 64
Thyroid hormones are essential for neural development, normal growth, sexual and skeletal maturation.
Thyroid hormones increase the rate of absorption of carbohydrates from gastrointestinal tract.
Thyroid hormones control basal metabolic rate and calorigenesis through increased oxygen consumption in tissue and enhanced mitochondrial respiration and oxidative phosphorylation.
Thyroid hormones stimulate adrenergic activity and leads to increased heart rate and mitochondrial contractility.
Thyroid hormones stimulate protein synthesis and carbohydrate metabolism, increases synthesis and degradation of cholesterol and triglycerides.
Thyroid hormones increase calcium and phosphorus metabolism.
THYROID FUNCTION TESTS:
Measurement of Thyroid Hormones
Initial approach to thyroid testing is to determine whether TSH is elevated, suppressed or normal. This is followed by measurements of circulating T3 & T4 levels to confirm the diagnosis of hypothyroidism
47
(elevated TSH) or hyperthyroidism (suppressed TSH). Measurement of circulating antibodies against thyroid peroxidase (TPO) and Thyroglobulin (Tg) is helpful in identifying Autoimmune thyroid disease. It is reasonable to measure only TPO antibodies because antibodies to Tg alone are uncommon. About 2% of euthyroid men and up to 5–15% of euthyroid women have thyroid antibodies. They are at increased risk of developing thyroid dysfunction. TPO antibodies are usually at higher levels in patients with autoimmune hypothyroidism and Graves’ disease.
Radioiodine Uptake study & Thyroid Scanning:
Thyroid Ultrasound
THYROID DYSFUNCTION: Thyroid dysfunction can be classified in to two forms
Hypothyroidism
Hyperthyroidism
HYPOTHYROIDISM:
Hypothyroidism results from deficient production of thyroid hormone.
It can result either from a defect in the gland itself or a result of reduced TSH/ TRH stimulation. Hypothyroidism can be classified into three forms as below
48
Subclinical hypothyroidism is defined as the laboratory evidence of thyroid hormone deficiency in individuals without any symptoms/signs of hypothyroidism.
CAUSES OF HYPOTHYROIDISM: 65
Iodine deficiency remains a common cause of hypothyroidism worldwide followed by autoimmune disease (Hashimoto’s thyroiditis).
PRIMARY HYPOTHYROIDISM:
Iodine deficiency
Autoimmune hypothyroidism: Hashimoto’s thyroiditis, Atrophic thyroiditis
Iatrogenic: 131I treatment, Subtotal or total thyroidectomy HYPOTHYROIDISM
PRIMARY SECONDARY TRANSIENT
49
Drugs: Lithium, Anti-thyroid drugs, p-aminosalicylic acid, Aminoglutethimide, Tyrosine kinase inhibitors (e.g., sunitinib)
Congenital hypothyroidism
Infiltrative disorders: Amyloidosis, Sarcoidosis, Hemochromatosis, Riedel’s thyroiditis
TRANSIENT HYPOTHYROIDISM:
Silent thyroiditis, including postpartum thyroiditis
Subacute thyroiditis
After 131I treatment or subtotal thyroidectomy for Graves’ disease
SECONDARY HYPOTHYROIDISM:
Hypopituitarism: tumors, pituitary surgery or irradiation, infiltrative disorders,
Sheehan’s syndrome, trauma, genetic forms of combined pituitary hormone deficiencies
Hypothalamic disease: tumors, trauma, infiltrative disorders, idiopathic
50
CLINICAL FEATURES OF HYPOTHYROIDISM:65
SYMPTOMS SIGNS
General weakness, Tiredness
Skin dryness, Loss of hair
Cold intolerance
Poor attention and memory
Constipation
Weight gain with poor appetite
Hoarse voice
Menorrhagia (later oligomenorrhea or amenorrhea)
Dry coarse skin
Puffy face, hands, and feet (myxedema)
Diffuse alopecia
Bradycardia
Peripheral edema
Delayed tendon reflex relaxation
Carpal tunnel syndrome
Serous cavity effusions
TREATMENT OF HYPOTHYROIDISM:65
CLINICAL HYPOTHYROIDISM: Daily replacement dose of Levothyroxine is usually 1.6 mcg/kg (around 100–150 mcg). It should be taken at least 30 min before breakfast.
51
SUBCLINICAL HYPOTHYRODISM: Treatment is administered by starting with a low dose of levothyroxine (25–50 mcg/day) with the goal of normalizing TSH. Levothyroxine is indicated in
Woman who wishes to conceive or is pregnant
TSH levels above 10 mIU/L.
TSH levels below 10 mIU/L, in patients with symptoms of hypothyroidism, positive TPO antibodies or any evidence of heart disease.
Figure 13: Algorithm for Evaluation of Hypothyroidism
52
HYPOTHYROIDISM & INFERTILITY:
Prevalence of hypothyroidism in the reproductive age group is 2–4%
and has been shown to be the cause of infertility and habitual abortion.66 Hypothyroidism causes increased production of TRH. This stimulates pituitary to secrete TSH and prolactin. Hyperprolactinemia in turn affects fertility by impairing GnRH pulsatility and hence ovarian function.
Figure 14: Factors promoting infertility in Hypothyroid women
Hypothyroidism can be detected by measuring Serum TSH levels.
Subclinical hypothyroidism is more common than overt hypothyroidism.67 Many infertile women with hypothyroidism had associated
53
hyperprolactinemia due to increased production of thyrotropin releasing hormone (TRH) in ovulatory dysfunction.68 Treatment should be first given to correct the hypothyroidism before evaluating other causes of elevated prolactin level.
Thyroid dysfunction in infertile women can be easily managed by correcting the appropriate levels of thyroid hormones.69 Hormone therapy with thyroxine is the choice of treatment in established hypothyroidism.
Levothyroxine treatment normalizes the menstrual cycle and improves the fertility rate. Levothyroxine replacement therapy in subclinical hypothyroidism is justified in infertile women, as normal TSH levels are necessary for fertilization. Thyroid function tests should be done in infertile women. Women having normal TSH levels, but positive for thyroid antibodies should also be treated with thyroxine replacement therapy.70
SUBCLINICAL HYPOTHYROIDISM (SCH) & INFERTILITY
Subclinical hypothyroidism is associated with ovulatory dysfunction.
Previous studies revealed variable data on prevalence of subclinical hypothyroidism in infertility, 25% by Bals Pratsch et al.,71 and 4.6% by Grassi et al. Verma et al showed that subclinical hypothyroidism was more common than overt hypothyroidism.72
54
Subclinical hypothyroidism (SCH) has recently been challenged as data have indicated that physiological free T4 (FT4) variations are narrower in one individual than those observed within the reference range of a population. These data might reflect an abnormally low FT4 value for patients who present a mildly increased serum TSH.73,74
Some authors have proposed restricting the upper normality limit of serum TSH to 2-5 mU/l. Today, however, there is no agreement among endocrinologists about the most appropriate (i.e. physiologically relevant) upper limit of normality for serum TSH.75
Figure 15: Studies on the prevalence of Subclinical hypothyroidism in infertile women
55
Bohnetet al., showed that subclinical hypothyroidism was considered as an infertility factor by itself. They showed that treatment with L- Thyroxine in infertile women normalized the mid progesterone secretion and 2/11 infertile women became pregnant.76 Bals-Pratschet al. did not observe corpus luteum insufficiency in infertile women with subclinical hypothyroidism.77
Gerhard et al. showed a positive correlation between basal TSH, LH and testosterone concentrations. Women having elevated serum TSH had a lower pregnancy rate than those women with a normal TSH level.78 Shalev et al., showed that the prevalence of subclinical hypothyroidism was 0.67%
in infertile women (all with ovulatory dysfunction).79 Grassiet al. noted that the mean duration of infertility was significantly longer in the patients with thyroid disorders compared to those without thyroid disorders.80 Arojoki et al. found that the prevalence of having an increased serum TSH was highest in the group with ovulatory dysfunction.81
In a case–controlled study, Poppe et al. investigated the prevalence of subclinical hypothyroidism (TSH > 4.2 mU/l) in women of infertile couples.
He showed that the prevalence of an increased serum TSH was comparable in both the study group and controls.82 Raber et al. showed that 34% of infertile women had subclinical hypothyroidism. Among the women who
56
became pregnant during the follow-up period, over 25% still had subclinical hypothyroidism. He also showed that the women who never achieved a basal serum TSH < 2·5 mU/l became pregnant less frequently than those who did.
Frequent abortions were observed in the women with a high serum TSH level.83
Overall, the studies investigating the association between subclinical hypothyroidism and infertility were poorly controlled. Considering the largest cohorts published, the prevalence of subclinical hypothyroidism in infertile women ranged from 1% to 4% and most cases with SCH were associated with ovulatory dysfunction.
THYROID AUTOIMMUNITY IN INFERTILITY
Autoimmune thyroid disease is the most common autoimmune disorder in women, affecting 5–10% in the childbearing period. It is also the most frequent cause of thyroid dysfunction. It can lead to either an overactive (Graves’ disease, hyperthyroidism) or underactive thyroid (Hashimoto’s thyroiditis, hypothyroidism).
Autoimmune thyroid disease occurs when the body makes antibodies that attack the thyroid and turn it on or off. This is characterized by positive
57
TPO and/or thyroglobulin antibodies. It is most commonly associated with in increased risk of developing hypothyroidism.
Women with positive TPO antibodies have been shown to have an increased risk of pregnancy complications, including miscarriage and preterm labor. Autoimmune thyroid disease has been shown to be more common in women seeking treatment for infertility.
Prevalence of thyroid autoimmunity is substantially higher among infertile women than fertile women (especially in infertile women with endometriosis and ovarian dysfunction). Autoimmune thyroid disease is seen most commonly in women between 30 to 50 years of age.
Forms of AITD:
Commonest forms of AITD are Hashimoto’s thyroiditis and Graves disease. Other forms include Atrophic autoimmune hypothyroidism, Postpartum thyroiditis and Thyroid associated orbitopathy
Prevalence of AITD:84
About 2 to 4 percent of women and up to 1% of men are affected worldwide, and the prevalence rate increases with advancing age.
58
Prevalence rate of autoimmune mediated hypothyroidism is about 0.8 per 100 and 95% among them are women.
Graves’disease is about one tenth as common as hypothyroidism and tends to occur more in younger individuals.
Scenario in India:
The true prevalence and incidence in India of thyroid disorders is difficult to estimate.
7.5% prevalence of autoimmune thyroiditis was demonstrable by fine needle aspiration biopsy among female goitrous students.
As India is now predominantly iodine sufficient we are nearing the peak prevalence of the autoimmune epidemic.
Thyroid Peroxidase
Thyroid peroxidase (TPO) is a key enzyme in thyroid hormone biosynthesis. Human TPO is located on chromosome 2p25, with 17 exons.
It catalyzes both iodination and coupling of iodotyrosine residues in TG.
59
Thyroid peroxidase (TPO) evokes high-affinity, IgG-class autoantibodies (TPOAb) and TPO-specific T cells. Anti-TPO antibodies can induce complement-dependent cytotoxicity.
TPO is a major antigen corresponding to thyroid-microsomal autoantibodies.
AntiTPO autoantibodies are very important to diagnose autoimmune thyroid diseases and also in estimating its clinical course.85
TPOAbs are positive in more than 90% of patients with Hashimoto’s thyroiditis, regardless of the presence of hypothyroidism or euthyroidism.
A case-control study showed that the relative risk of positive TPO antibodies in infertile women and in particular related to endometriosis is significantly increased.
Diagnosis of AITD: Indian Thyroid Guidelines 2011
Tests for antibodies against Thyroid peroxidase (TPOAb), Thyroglobulin (TgAb) and TSH receptors (TRAb) are used in the diagnosis of autoimmune thyroid disorders.
60
Associated features of AITD in infertile women:
61
Figure 17: Algorithm for the screening of thyroid dysfunction and autoimmunity in infertile women.86
Following studies have investigated the prevalence of autoimmune thyroid disease in women with infertility.
62
Figure 18: Relevant studies of AITD in infertile women
In the case–controlled study by Poppeet al., comparing women of infertile couples with age-matched fertile women, the relative risk of AITD reached 3·57 (P =0·016) when women had endometriosis as the cause of infertility.82
Gerhard et al. showed that 44% of women with AITD had endometriosis.78 Janssen et al., showed a strong association between AITD and women with polycystic ovarian syndrome (PCOS) (as the cause of infertility)87 This association correlated with an increased oestrogen/progesterone ratio characteristic for this syndrome. These studies showed a strong association between AITD and a particular cause of infertility.
63
HYPERTHYROIDISM:
Hyperthyroidism is the result of excessive thyroid function.
Thyrotoxicosis is a state of thyroid hormone excess. The major etiologies of
thyrotoxicosis are hyperthyroidism caused by Graves’ disease, toxic multinodular goiter (MNG), and toxic adenomas.
CAUSES:65
Primary Hyperthyroidism
Graves’ disease
Toxic multinodular goiter
Toxic adenoma
Jod-Basedow phenomenon – Iodine excess
Secondary Hyperthyroidism
TSH-secreting pituitary adenoma, Chorionic gonadotropin-secreting tumors
Gestational thyrotoxicosis
64
Thyrotoxicosis without Hyperthyroidism
Subacute thyroiditis
Thyrotoxicosis factitia – Ingestion of excess thyroid hormone or thyroid tissue
CLINICAL FEATURES OF HYPERTHYROIDISM:65
SYMPTOMS SIGNS
Palpitations
Sweating, heat intolerance
Loss of weight with increased appetite
Polyuria, Diarrhea
Loss of libido
Oligomenorrhea
Tachycardia
Atrial fibrillation
Tremor
Goiter
Lid retraction
Gynecomastia
TREATMENT:
Antithyroid drugs - Propylthiouracil, Carbimazole,Methimazole
Radioiodine (131I) treatment
Thyroidectomy
65
Antithyroid drugs:65 They inhibit the function of TPO, reducing oxidation and organification of iodide.
Dosage:
Carbimazole/Methimazole: 10–20 mg every 8 or 12 h, (once-daily dosing after euthyroidism is restored),
Propylthiouracil: 100–200 mg every 6–8 h.
To control adrenergic symptoms: Propranolol (20–40 mg every 6 h) or Atenolol
Radioiodine: It causes progressive destruction of thyroid cells and can be used as initial treatment or for relapses after a trial of anti-thyroid drugs.
Total or near-total thyroidectomy: This is an option for patients who relapse after anti-thyroid drugs and prefer this treatment to radioiodine.
66
Figure 19: Algorithm for Evaluation of hyperthyrodisim
HYPERTHYROIDISM & INFERTILITY:
Hyperthyroidism plays a significant role in both male and female infertility. It is estimated that approximately 5.8% of women who have either primary or secondary infertility have a diagnosis of hyperthyroidism.88,89
