Menstrual irregularities and lactation failure may precede thyroid dysfunction or goitre.JV Joshi, SD Bhandarkar, M Chadha, D Balaiah, R Shah
Institute for Research in Reproduction, Seth GS Medical College, Parel, Bombay, Maharashtra.
Menstrual and reproductive history of 178 women referred to the thyroid clinic was compared with 49 healthy controls. Cases were classified as euthyroid, hypothyroid or hyperthyroid after clinical examination and after serum T 3 , T 4 , TSH measurements. Reproductive history was related chronologically to symptoms and signs of thyroid dysfunction. Only 31.8% of hypothyroid and 35.3% of hyperthyroid women had normal menstrual pattern in contrast with 56.3% of Euthyroid and 87.8% of healthy controls (p < 0.001). Reproductive failure (infertility, pregnancy wastage, failure of lactation) occurred in 37.5% of hypothyroid and 36.5% of hyperthyroid cases against 16.3% of euthyroid and 16.7% of healthy controls (p < 0.05). Interestingly, in 45% of cases with menstrual abnormality, the anomaly was antecedent to other clinical features by a variable period of two months to ten years. Reproductive failure and lactation failure also preceded thyroid dysfunction or goitre. Reproductive dysfunction may therefore be considered as one of the presenting symptoms of thyroid disorders in women, keeping in mind both menstrual irregularities and lactation failure may also arise from other common or idiopathic origins. Especially in women with menstrual irregularities in the perimenopausal age if thyroid dysfunction is detected, pharmacotherapy may be a superior alternative to surgical interventions like hysterectomy.
Keywords: Menstrual cycles, thyroxine, thyroid stimulating hormone, reproductive function abnormalities.
Thyroid dysfunction is known to affect all aspects of reproductive function in the female. Hypothyroidism or hyperthyroidism can produce infertility, abortions, stillbirths, failure of lactation and menstrual abnormalities - . Most authors have described the clinical picture in established hypo / hyperthyroidism ,,,,, . However some workers have reported the occurrence of infertility  , premenstrual syndrome  and menorrhagialo in women with early and subclinical hypothyroidism. It has been stated that menorrhagia is more common in hypothyroidism or myxoedema, whilst anovulation or oligomenorrhea is common in hyperthyroidism ,,,,, . 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 goitre or clinical symptoms and signs are present. The need to investigate thyroid function in the absence of clinical symptoms and signs, and in the absence of goitre, is less well recognised. The aim of this study was to determine the proportion of cases with thyroid disorders having menstrual irregularity, pregnancy wastage and lactation failure, and to determine whether these abnormalities could precede other clinical manifestations of thyroid dysfunction.
A total of 178 women between the age of 13 and 46 years, and who were referred to the Thyroid clinic of the KEM Hospital between January to April 1991, were included in the study. Healthy young females 49 in number, who attended the Family Planning Clinic of the Institute for Research in Reproduction, during the same period were registered as healthy controls. The menstrual, obstetric and lactation data was recorded and analysed by gynaecologists, whilst the thyroid functions tests were carried out by the endocrinologists. Women were classified into 4 groups:
Group 1. Euthyroid cases (N = 87): Women with an enlarged thyroid gland but without symptoms and signs of thyroid dysfunction and with triiodothyronine (T 3 ), tetraiodo-thyronine (T 4 ) and thyroid stimulating hormone (TSH) levels within normal limits.
Group 2. Hypothyroid cases (N=22): Women with or without goitre but with clinical and laboratory features of hypothyroidism (T 3 / T 4 decreased, TSH raised)
Group 3. Hyperthyroid cases (N=69): Women with or without goitre but with clinical and laboratory features of hyperthyroidism (T 3 / T 4 increased, TSH decreased)
Group 4. Control cases (N=49): Healthy women without any goitre and without any clinical symptoms and signs of thyroid dysfunction (T 3 , T 4 , TSH not done)
The normal range of thyroid hormone levels in our laboratory using standard radioimmunassay procedures is as following: T 3 - 70 to 200 / mg %; T4 - 5.5 to 13.5 /mg %; TSH - 0.2 to 5 /mUml. Other investigations like thyroid scan, fine needle aspiration biopsy, ultrasound, or X-ray neck were carried out as required. None of these women had any other systemic illness with the exception of an old treated pulmonary tuberculosis. Eleven women had undergone subtotal thyroidectomy in the past. One case had normoprolactinaemic galactorrhoea.
All cases were investigated using a uniform protocol, which included medical, surgical and obstetric history, and clinical examination. Lactation failure was defined as the need to start top feeds for the baby within 3 months of delivery because of inadequate breast milk supply. Working women who initiated top feeds early with the intention of joining duty were excluded from this category. Cases of hyperthyroidism who were advised to discontinue lactation due to treatment with antithyroid drugs were also excluded. Normal menstrual cycles were defined as those with a length of 22 to 40 days and moderate bleeding for 3 to 7 days. Women with more than 90 days of amenorrhoea were classified as secondary amenorrhoea. The menstrual and obstetric history was analysed group wise. Current menstrual history refers to the menstrual pattern within 6 months of diagnosis.
The statistical test applied was the standardised normal deviate (Z test) for testing the differences between the proportions.
The mean age, age at menarche, parity and marital status of all women were comparable in all groups. The duration of the clinical symptoms or signs like swelling in the neck was less than 12 months in 44.8% of cases, 13-14 months in 18.8% of cases and more than 24 months in 36.4% of cases.
When past menstrual history was analysed it was observed that more than 70% of hyperthyroid and control cases reported normal menstrual cycles as compared to 54.6% of hypothyroid and 59.3% of euthyroid cases. The differences between the groups were not statistically significant.
When current menstrual history was analysed [Table - 1] it was observed that 88% of control had normal pattern and none had secondary amenorrhoea. Only 32.4% of cases with hypolhyper- thyroidism had a normal menstrual cycles. It was interesting to see that 44% of euthyroid cases also had an abnormal menstrual pattern. All types of menstrual abnormalities were common, not only with thyroid dysfunction but also in so called functionally euthyroid cases in whom the only other anomaly was presence of a goitre. These differences were statistically significant (p < 0.05). Amongst the menstrual abnormalities, oligo/hypomenorrhoea was most common, whilst secondary amenorrhoea was uncommon. All types of bleeding irregularities were seen either in hypo or hyper-thyroidism.
[Table - 2] depicts the percentage of women with infertility, abortions, stillbirths and early neonatal deaths in each group. A large percentage of cases with thyroid disorders (34-37%); had reproductive failure as compared to the controls (16.7%), however the difference was significant only for the hyperthyroid group (p<0.05). The percentage in euthyroid group was similar to that in controls (19.3% and 16.7%).
The onset of menstrual abnormality was analysed chronologically with respect to the onset of the thyroid swelling or other clinical symptoms and signs [Table - 3]. In more than 45% of cases in the study groups (euthyroid, hypothyroid, hyperthyroid) the menstrual abnormality occurred before the onset of disease. In the remaining it started along with the disease or later. Of particular interest was the finding that even in euthyroid cases the menstrual abnormality preceded the swelling in the neck as reported by the patient in 47% of cases. Thus out of 45 cases, in whom the menstrual disorder preceded thyroid dysfunction, 13 occurred within 1 year, 16 occurred in 2 to 5 years and another 16 were noted 6 to 10 years earlier to the appearance of the goitre or symptoms and signs of thyroid abnormality.
The number of times lactation failure was reported in relation to the total live births is given in [Table - 4]. Hyperthyroid cases who were advised to stop breast feeding due to anti-thyroid therapy were excluded from this analysis. Although 16.7% of controls also reported lactation failure it was observed more frequently with hypo / hyperthyroidism (18.6 to 31.3%). Lactation failure, more than once, was reported less commonly but it is significant that it was observed only with thyroid disorders and never with control cases.
The onset of lactation failure was analysed with respect to the advent of the disease. In 21 out of 28 (75%) cases of lactation failure, the event occurred before the swelling in neck was noticed or other symptoms and signs of disease were evident. In the remaining, 25% of cases it occurred simultaneously with or after the onset of disease.
Out of 21 cases of failure of lactation which preceded the thyroid disorders, 9 cases preceded by a period of 2 months to 5 years, and 12 cases by a period of 5 to 10 years, Overall in 33 cases, reproductive failure, as defined earlier, occurred prior to the onset of thyroid disorder. Unmarried, separated, divorcees and contraceptive users were excluded from this analysis. In 14 cases it preceded by a period upto 5 years, and in 19 cases it preceded by a period of 5 to 10 years.
Reproductive function in women can be altered by thyroid disorders. Menstrual abnormality is known to occur in overt hypo / hyperthyroidism. Menorrhagia is reported to occur in 32-56% of cases of myxoedema ,,, . The mechanisms through which reproductive dysfunction occurs are multiple e.g. altered TRH response, altered LH response, peripheral conversion of androgens to estrogens, change in androstendione metabolism, catecholoestrogens, altered sex hormone binding globulin levels ,,,,, .
The Occurrence and mechanism of menstrual disorders in thyroid dysfunction have been described but there are no reports on their prevalence in functionally euthyroid women presenting with a goitre - . Although Ross et al  reported severe uterine bleeding in 2 cases of unrecognised myxoedema both women had typical features of hypothyroidism like dry skin, bradycardia, puffiness of skin and delayed tendon reflexes. On the other hand in the present study the euthyroid group with goitre did not have any of these features and were not advised treatment for thyroid dysfunction. Yet 44% had menstrual abnormality. This suggests that this symptom may be observed in preclinical stages of thyroid dysfunction. Subclinical hypothyroidism is an entity where T 3 , T 4 levels and clinical picture are normal or ambiguous and TSH levels are raised. Buxton and Herrman  as early as 1954 described 23.8% of cases of infertility treated with thyroid who became pregnant as compared to 10.7% in the placebo group, though the difference was not statistically significant. Theoretically in some cases TSH levels cans also be normal but the TRH response may be altered. Recent literature indicates that this may cause reproductive dysfunction. Brayshaw and Brayshaw  reported that out of 54 cases of premenstrual syndrome 35 had subclinical hypothyroidism as evidenced by abnormal TSH stimulation test. They further observed clinical relief of symptoms in 34 out of 54 women who had been treated with levothyroxine. Wilansky and Greisman  detected abnormal TRH response in 15 out of 67 euthyroid cases with menorrhagia. The TSH level was within normal limits (10/ mU/ml). Out of these, 8 women responded to 1-thyroxine treatment biochemically as well as clinically. Bohnet et al  observed that subclinical hypothyroidism could be demonstrated in 20 out of 150 cases of infertility. Two women conceived after treatment with thyroxine. Singh et al  have reported that out of 47 infertile, apparently euthyroid women, 20 cases had subclinical hypo/ hyper-thyroidism. Nath and coworkerss observed that 18.3% of infertile cases had abnormal T 3 , T 4 levels.
In the present study we have observed that all types of menstrual abnormalities were significantly more frequent in women with hypo-or hyperthyroidism as compared to control cases (p < 0.001). Even more important was the finding that 38 out of 87 cases with goitre, diagnosed as functionally euthyroid, had abnormal menstrual pattern as compared with 6 out of 49 controls (p < 0.001). Another striking feature was that in more than 45% of cases with hypo/hyperthyroidism the menstrual abnormality preceded the appearance of goitre or clinical symptoms and signs, sometimes by a period of several years. A similar observation was made in the euthyroid group. We therefore surmise that any type of menstrual disorder should be considered as a possible presenting symptom of thyroid dysfunction and it may indicate subclinical abnormality. In some cases, T 3 , T 4 , TSH levels may be within normal limits and only the TRH response may be altered. Such a situation may be observed prior to the development of goitre. Similarly, we observed that infertility or lactation failure, particularly repeated lactation failure, might precede the observation of swelling in the neck or clinical features of thyroid dysfunction. Other causes of lactation failure, particularly with respect to previous deliveries, could not be excluded in this study eg. infections, hypopituitarism, psychiatric disorders etc. Many cases are often labelled as idiopathic. It was remarkable that all cases with repeated failure of lactation in successive 2 or 3 deliveries were in the control group. Hence at least in some of seemingly idiopathic cases subclinical thyroid dysfunction should be excluded by sensitive tests like the TRH stimulation test if it is available. The importance lies in a high level of suspicion index and being able to treat the cause easily, this being tremendously advantageous to the mother and newborn.
The prevalent medical literature does not list menstrual irregularity or lactation failure as a presenting symptom of thyroid dysfunction, particularly in the absence of a goitre ,, . Although thyroid function tests are described in women with infertility or menstrucil disorders many physicians do not advise them if functionally the subject is euthyroid. Recent studies indicate that subclinical hypothyroidism cannot be excluded merely on the basis of normal T 3 , T 4 and even normal TSH levels. A control group, similar in age, age at menarche, parity and marital status was included for comparison. The findings of this study therefore suggest that reproductive dysfunction in women should be considered as one of the presenting symptoms because it may precede the appearance of goitre in a substantial proportion of cases. Although literature reports say that menorrhagia is more common in hypothyroidism and amenorrhoea or oligomenorrhoea in hyperthyroidism, our observations did not confirm this. Any type of menstrual irregularity can occur with either hypo or hyperfunction of the thyroid. Investigations for thyroid dysfunction cannot be advised as a routine, but need to be carried if surgery, for example hysterectomy, repeated laparoscopy or wedge resection is being considered. The prompt response to treatment with thyroxine will not only preclude unnecessary surgery but will also prevent clinical thyroid disorder at a later date. Women presenting with menstrual irregularities or reproductive dysfunction are usually investigated for thyroid functions. The tests should include TSH, TRH stimulation test if feasible.
We are thankful to the Dean, King Edward Memorial Hospital and GS Medical College for allowing us to present this data.
[Table - 1], [Table - 2], [Table - 3], [Table - 4]