Posts Tagged ‘Graves’ disease’

The Experience of a Patient with Thyroid Cancer

Interviewer and Curator: Larry H Bernstein, MD, FCAP


Thyroid cancer is usually a fairly innocuous disease, but it can present in different ways. There are are perhaps two main types – medullary, and follicular.  But an anaplastic type is also a third uncommon type.  It is speculative for me to suggest that the anaplastic type is a progression of either of the two main types.  A RAS genotype coexists with the aggressive anaplastic carcinoma.  Thyroid cancers are BRAF positive in genotype.  The histological feature that is used to identify this neoplasm is the presence of “sammoma bodies”.  It is more common in women, and less common in the elderly, and the incidence appears to have increased regionally in recent years.  A recent paper suggests a common specific feature with breast cancer, which is unconfirmed.

When we consider thyroid disease, we start with euthyroid status, hypothyroid and hyperthyroid, all of which are related to the synthetic activity of the gland, that has a right and left lobe joined by a isthmus.  In the midwestern US there is a deficiency of iodine, which leads to nodular thyroid goiter.  The Mayo brothers pioneered in thyroid surgery at their clinic in Rochester, MN.  This led to the insertion of iodine in table salt (Morton’s salt- “when it rains, it pours).  Hyperthyroid status is over production of the hormone by an overactive gland. It is usually primary disease, called Grave’s Disease, after the physician who described it. I am not aware of the occurrence secondary to hyperactivity of the pituitary gland, which would result in both an increased thyroid stimulating hormone (TSH), thyrotropin, and elevated thyroid hormone, except by a primary neoplasm of thyrotropin secreting cells.  The two hormones are under feedback control.  This feedback is a valuable diagnostic indicator because the TSH is suppressed with Grave’s disease.  The TSH assay is very accurate, and as the TSH falls, the TH increases, but the TH assay has never been as accurate as the TSH. The TH is transported in serum by three proteins: thyroxin-binding globulin (TBG), albumin, and trans-thy-retin (TTR), a quadruplex peptide with one subunit binding to retinol-binding protein (RPB), which transports retinol, vitamin A).  The importance of TTR is not a subject for discussion here, but it has extremely important ties to metabolic disease that includes hyperhomocysteinemia and Alzheimer’s disease, as this protein is produced by both the liver and the choroid plexus, but the CP production declines in the elderly.  The TTR metabolism is closely linked to total body sulfur, measured by K+ isotope measurement of lean body mass (fat free mass), and is a more accurate measure than use of urinary creatinine loss, which only measure the structural body mass, but not the visceral component.

There is another twist to the story in that thyroid hormone may be depressed over time secondary to an autoantibody to thyroid “peroxidase”, leading to destruction of the gland.  The thyroid antibody that occurs has been recently reported to be a “peroxidase” antibody in common with the mammary gland.  The disorder is denominated – Hashimoto’s thyroiditis. The presence of thyroid antibody may occur with Grave’s disease, with an occular protrusion with inflammation of the adductor muscles of eye movement.  This is termed “exophthalmus”.  However, thyroid eye disease is known to occur with hypo-, hyper-, and euthyroid status.

I here describe the long and difficult search to identify a confusing case.


Family history: Mother had thyroid cancer, surgically cured at Mayo Clinic. Sister had Hashimoto’s thyroiditis. Father had severe rheumatoid arthritis.

History of Illness.  The patient is a male over 65 years age who attended a discussion group for several years and participated in supervised fitness exercises and did daily walks for 2-3 years prior to the discovery of the problem when he recalls, his voice was weak in making presentations to the discussion group (age 86 and over).

At the end of summer, 2013, he experienced shortness of breath and dizziness on walking.  His physician had been concerned about the change of voice prior to this.  He had a history of sleep apnea, and he was actively trying to lose weight.  Cardiac and vascular examination of carotid and of peripheral circulation were unexpectedly excellent.  Pulmonary studies were good.

A visit to an ENT physician did not explain the voice impairment.  An unexpected low TSH result came back < 0.01, compared to a normal result 9 months earlier. This was the first indication of an active cyst or Grave’s disease. The patient was referred for ultrasound exam, and a thyroid panel was ordered.  The result of the ultrasound was an enlarged right lobe with two large degenerate cysts, and a central small calcified cyst.  The cyst was biopsied and it was malignant. It was BRAF pos and RAS negative.

He was referred to the nearest world-class academic center for further endocrine evaluation.  The endocrinologist palpated a thyroid enlargement, and a biopsy was performed of the lymph nodes under a full scan of the neck.  Surgery was scheduled and a surgeon skilled in endocrine surgery and cancer removed the thyroid, and noted that the right lobe compressed the recurrent laryngeal nerve.  This was consistent with en ENT examination of the larynx that showed paralysis of the right larynx.  The good news was that the prediction was that the nerve innovation was good, and would return.

There were a few involved lymph nodes in the removed specimen. The patient was put on synthroid. The next step was to schedule I131 radioiodine treatment by oral tablets.  This required a preparatory diet of no salt or iodine intake prior to treatment.  There was also a 5 day isolation for beta ray emission (which kills residual thyroid cells).  The neck was scanned with a gamma scanned prior to induction of treatment, which required a dose of synthetic TSH and a low dose of I131.   The patiemt is recovered for 14 days post treatment and has regained much energy.

There is a residual burden of the thyroid eye disease that requires special optical care because of loss of distance perception with diplopia.  This is stable, but any surgical repair would have to wait for a year.


Notes from PathologyOutlines.com, Nathan Pernick, Editor-in-Chief

Thyroid gland

Reviewer: Zubair W. Baloch, M.D., Shahidul Islam, M.D., Ph.D., Ricardo R. Lastra, M.D., Michelle R. Pramick, M.D., Phillip A. Williams, M.D., MSC (see Reviewers page)

Revised: 11 July 2014, last major update IN PROGRESS
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.

Endocrine abnormalities and thyroid gland

Reviewer: Shahidul Islam, M.D., Ph.D.


  • Accelerated thyroid hormone biosynthesis and secretion by thyroid gland
  • Early symptoms: anxiety, palpitations, rapid pulse, fatigue, muscle weakness, tremor, weight loss, diarrhea, heat intolerance, warm skin, excessive perspiration, menstrual changes, hand tremor
  • Ocular changes: wide staring gaze and lid lag due to sympathetic overstimulation of levator palpebrae superioris

Thyrotoxicosis: hypermetabolic clinical syndrome due to elevated serum T3 or T4


  • Primary hyperthyroidism: intrinsic thyroid abnormality
    • Low TSH, high free T4, normal TRH stimulation test
  • Secondary hyperthyroidism: high TSH, abnormal TRH stimulation test
  • Subclinical hyperthyroidism: low TSH (< 0.1 µIU/ml), normal T3 and T4 (Eur J Endocrinol 2005;152:1), no clinical hyperthyroidism
  • T3 hyperthyroidism: 1-4%ofhyperthyroid patients
    • Low TSH, high free T3, normal free T4
    • Associated with early treatment of hyperthyroidism with antithyroid drugs
  • T4 hyperthyroidism:highT4, normal T3

Graves’ disease (85%)

Micro images

Diffuse hyperplasia of thyroid gland

Additional references

Hashimoto’s thyroiditis


  • Autoimmune disease with goiter, elevated circulating anti-thyroid peroxidase and anti-thyroglobulin antibodies
  • First described by Hakaru Hashimoto in 1912 (World J Surg 2008;32:688)


Clinical features

Clinical features

  • Adults present with painless, gradual thyroid failure due to autoimmune destruction, may initially have transient hyperthyroidism
  • Children have variable hypothyroidism and reversion to euthyroidism so must monitor thyroid function (Clin Endocrinol (Oxf) 2009;71:451)
  • Associated with HLA-DR5 (goitrous form), HLA-DR3 (atrophic form)
  • May coexist with SLE, rheumatoid arthritis, Sjögren’s syndrome, pernicious anemia, type 2 diabetes, Graves’ disease, chronic active hepatitis, adrenal insufficiency, MALT lymphoma of gastrointestinal tract (80:1 relative risk), other B cell lymphomas
  • Associated with well differentiated thyroid cancer (J Am Coll Surg 2007;204:764)
  • May evolve into thyroid lymphoma (J Clin Pathol 2008;61:438)



  • Autoantibodies include:
    • Anti-TSH (specific for Hashimoto’s and Graves’ disease)
    • Anti-thyroglobulin (less sensitive but similar specificity as anti-thyroid peroxidase, Clin Chem Lab Med 2006;44:837)
    • Anti-thyroid peroxidase (previously called antimicrosomal antibody, sensitive but not specific as 20% of adult women without disease have these antibodies); anti-iodine transporter (rare)
    • Note: anti-TSH antibodies block the TSH receptor in Hashimoto’s disease but stimulate the TSH receptor in Graves’ disease

Papillary carcinoma

  • 75-80% of thyroid carcinomas
  • Occult tumors in 6% at autopsy (1 to 10 mm), 46% multicentric, 14% with nodal metastases (Am J Clin Pathol 1988;90:72)
  • Occult tumors in up to 24% with other thyroid disease, but with male predominance (Mod Pathol 1996;9:816)


  • Usually women (70%) of reproductive age

Clinical features

Prognostic factors

  • 10 year survival is 98%, similar to general population (versus 92% for follicular carcinoma); 100% if under age 20, even with nodal metastases
  • Cervical nodal involvement does NOT affect prognosis
  • 5-20% have local recurrences, 10-15% have distant metastases (lung, bones, CNS)
  • Poorer prognosis:
    • Age 40+ or elderly, male (possibly), local invasion (associated with higher incidence of nodal metastases, Arch Pathol Lab Med 1998;122:166), distant metastases (other sites worse than lung, Surgery 2008;143:35), large tumor size, multicentricity, tall cell, columnar or diffuse sclerosing variants
    • Poorly differentiated, anaplastic or squamous foci

added July 14, 2014

Summary – Intraoperative laryngeal nerve monitoring
Objectives: The aim of this study was to stimulate the recurrent laryngeal nerve during thyroidectomy or parathyroidectomy and to record the muscle responses in an attempt to predict postoperative vocal fold mobility.
Patients and methods: Intraoperative recurrent laryngeal nerve monitoring during general anaesthesia was performed by using an electrode-bearing endotracheal tube (nerve integrity monitor EMG endotracheal tube [Medtronic Xomed, Jacksonville, Flo, USA]). Two hundred and fifteen recurrent laryngeal nerves from 141 patients undergoing total thyroidectomy (n = 74),
hemithyroidectomy (n = 63), or parathyroidectomy (n = 4) were prospectively monitored. In each case, the muscle potential was recorded after stimulation of the recurrent laryngeal nerve by a monopolar probe.
Results: The nerve stimulation threshold before and after dissection that induced a muscle response of at least 100 V ranged from 0.1 to 0.85 mA (mean 0.4 mA). The supramaximal stimulation intensity was defined as 1 mA. The amplitude of muscle response varied considerably from one patient to another, but the similarity of the muscle response at supramaximal intensity between pre- and postdissection and between postdissection at the proximal and distal exposed
portions of the nerve was correlated with normal postoperative vocal fold function. Inversely, alteration of the muscle response indicated a considerable risk of recurrent laryngeal nerve palsy, but was not predictive of whether or not this lesion would be permanent.  http://dx.doi.org:/10.1016/j.anorl.2011.09.003

Summary – Prognostic impact of tumour multifocality in thyroid papillary microcarcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 175—178

Objective: The objective of this study was to evaluate the prognostic impact of tumour multifocality in papillary thyroid microcarcinoma (PTMC).
Methods: All patients who underwent total thyroidectomy and central neck dissection for PTMC in our institution between 1990 and 2007 were included in this retrospective study. Statistical correlations between tumour multifocality and various clinical or pathological prognostic parameters were assessed by univariate and multivariate analyses.
Results: A total of 160 patients (133 women and 27 men; mean age: 47.8 ± 13.7 years) were included in this study. Tumour multifocality was demonstrated in 59 (37%) patients. Central neck metastatic lymph node involvement was identified in 46 (28%) patients. No statistical correlation was demonstrated between tumour multifocality and the following factors: age, gender, tumour size, extension beyond the thyroid, metastatic central neck lymph node involvement and risk of recurrence. A tumour diameter greater than 5 mm was associated with a higher risk of recurrence (P = 0.008).
Conclusion: Tumour multifocality does not appear to have a prognostic impact in PTMC.   http://dx.doi.org:/10.1016/j.anorl.2011.11.003

Positron emission tomography thyroid carcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 251—256

Objectives: Recurrence is observed in 15—20% of patients under surveillance following treatment of differentiated thyroid cancer (DTC). However, due to cell dedifferentiation, the recurrence may be iodine-negative, thereby compromising detection. For this reason, new methods of exploration are indispensable to enable localization of such recurrences. The purpose of this work is to review the contribution of positron emission tomography—computed tomography (PET-CT) in the exploration of iodine-negative recurrent DTC.
Method: A comprehensive review and discussion of the medical literature was carried out.
Results: Depending on the report, the sensitivity of PET-CT ranged from 70% to 85%, with up to 90% specificity. However, the large number of false negatives, which can reach 40%, is the
disadvantage of this examination. PET-CT results lead to change in the therapeutic strategy in approximately 50% of patients with isolated raised serum thyroglobulin levels, and surgical exploration of a precise anatomical area in the neck.
Conclusion: As post-treatment recurrence of a DTC can affect patient survival, a thorough diagnostic work-up is required in these cases. Where thyroglobulin levels are elevated with no uptake on 131-iodine scans, PET-CT can be a useful complementary exploration, especially for localizing the site of recurrence.
French ENT Society (SFORL) practice guidelines for lymph-node management in adult differentiated thyroid carcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 197—206

Cervical and mediastinal lymph-node management differentiated thyroid carcinoma of the follicular epithelium (DTC) remains controversial. Depending on the situation, pre-operative staging and indications for and extent of lymph-node dissection are still matters of debate, even in case of palpable nodes found on primary surgery. Procedural indications for adenectomy, selective neck dissection, and anatomic regional extension of dissection are not clearly defined.

Questions raised:

• what is lymph-node involvement in DTC?
• what is the prognostic value of lymph-node invasion: for
recurrence, and for survival?

• what baseline assessment is required ahead of treatment
of papillary thyroid carcinoma to assess possible lymphnode

• what are the principles of lymph-node surgery?
Central and lateral dissection, and dissection extended to the mediastinum;
• what is the iatrogenesis in cN0 and cN+ neck?
• what is the impact of central and lateral neck dissection on recurrence, survival, secondary treatment and surveillance in cN0 and cN+ ?
• in cN0 patients, when neck dissection is considered, what lymph-node regions should be indicated?
http://www.orlfrance.org/ download.php?id=159.

Molecular Diagnosis for Indeterminate Thyroid Nodules on Fine Needle Aspiration
Expert Rev Mol Diagn. 2013;13(6):613-62

Somatic mutation testing, mRNA gene expression platforms, protein immunocytochemistry and miRNA panels have improved the diagnostic accuracy of indeterminate thyroid nodules, and although no test is perfectly accurate, in the authors’ opinion, these methods will most certainly become an important part of the diagnostic tools for clinicians and cytopathologists in the future.

Several point mutations and gene rearrangements have been identified in thyroid cancer. The most common somatic mutation in differentiated thyroid cancer  has been studied as a potential tool to enhance the diagnostic accuracy of indeterminate FNA lesions – BRAF. This mutation occurs in papillary, poorly differentiated and anaplastic thyroid cancer and causes a V600E substitution in the BRAF protein, which results in neoplastic progression by aberrant activation of the MAPK pathway. The BRAF V600E mutation, along with RET/PTC rearrangements, are a hallmark of thyroid cancer and a vast majority of indeterminate thyroid nodules harboring either one of these two mutations are malignant on final pathology.

The RAS proto-oncogene encodes three different membrane associated GTP proteins: HRAS, KRAS and NRAS. Mutation of these domains causes increased signal transduction through both the MAPK and the PI3K/AKT pathways. These mutations are highly prevalent in FTC and in the follicular variant of papillary thyroid cancer (40–50%) and seldom detected in the classic variant papillary thyroid cancer (10%). RAS mutations have also been identified in benign FA; however, it is unclear whether RAS-positive FA have a higher chance of progression to cancer.

Recurrence detection in differentiated thyroid cancer patients..
Clinical endocrinology, Vol. 72, No. 4. (10 September 2009), pp. 558-563, doi:10.1111/j.1365-2265.2009.03693.x

There was a correlation between TgAb level and recurrence (p = 0.032).
). Recurrence was found in 37.5% of 24 TgAb+/Tg- patients who showed a gradually increasing tendency in serial measurements of TgAb. Sixteen cervical foci (21.1%) missed on neck USG and 17 lesions (22.4%) located outside the neck were additionally detected with PET/CT in TgAb+ patients.

Solving the mystery of iodine uptake
Science 20 June 2014: Vol. 344 no. 6190 p. 1355    http://dx.doi.org:/10.1126/science.344.6190.1355-a

The cell membrane protein NIS (sodium/iodine symporter) transports iodine into thyroid cells, but because iodine concentrations outside of the cell are so low, how it does so is a mystery. The key? Moving two sodium ions along with the iodine ion, Nicola et al found. NIS also does not bind sodium very tightly, but the high concentrations of sodium outside the cell allow one sodium ion to bind. This binding increases the affinity of NIS for a second sodium ion and also for iodine. With the three ions bound, NIS changes its conformation so that it opens to the inside of the cell, where the sodium concentration is low enough for NIS to release its sodium ions. When the sodium goes away, so does NIS’s affinity for iodine, leading NIS to release it.











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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Increasing evidence derived from experimental and clinical studies suggests that the hypothalamic–pituitary–thyroid axis (HPT) and the hypothalamic–pitutitary–ovarian axis (HPO) are physiologically related and act together as a unified system in a number of pathological conditions. The suggestion that specific thyroid hormone receptors at the ovarian level might regulate reproductive function, as well as the suggested influence of estrogens at the higher levels of the HPT axis, seems to integrate the reciprocal relationship of these two major endocrine axes. Both hyper- and hypothyroidism may result in menstrual disturbances. In hyperthyroidism the most common manifestation is simple oligomenorrhea. Anovulatory cycles are very common. Increased bleeding may also occur, but it is rare. Hypothyroidism in girls can cause alterations in the pubertal process; this is usually a delay, but occasionally it can result in pseudoprecocious puberty. In mature women hypothyroidism usually is associated with abnormal menstrual cycles characterized mainly by polymenorrhea, especially anovulatory cycles, and an increase in fetal wastage.

Thyrotoxicosis and the female reproductive system
Increased sex hormone-binding globulin (SHBG) concentration is characteristic of hyperthyroidism so much so that this globulin is used as a test of thyroid function, reflecting the tissue response to the thyroid hormones. Serum levels of estradiol and testosterone should thus be interpreted with this fact in mind because their total amounts are increased out of proportion to the free levels. Also, women with thyrotoxicosis have a decrease in the metabolic clearance rates of testosterone and of estradiol, an increase in the 5α/5β-reduced metabolites in the urine, and an increase in catechol estrogens in the urine at the expense of estriol and other 16-hydroxylated estrogen metabolites. Southern et al. have found an increase in the peripheral aromatization of androgens to estrogens in some thyrotoxic women. Other studies, however, did not confirm these findings and suggested that any increase in the peripheral aromatization of androgens is likely to be due to an increase in the peripheral blood flow and and not to the direct effect of T4 on the aromatase complex. One of the earliest clinical changes observed in thyrotoxicosis was the occurrence of amenorrhea, which was first reported in 1840. Amenorrhea has been reported frequently since then, but a number of other changes in menstrual cycles have been noted, including anovulation, oligomenorrhea, and menometrorrhagia, which is more common in hypothyroidism. Whether these changes are due to a direct action of T4 on the ovary and uterus or on the pituitary and hypothalamus or both is uncertain. The effect of T4 on fertility is less well established, although the disturbances in menstrual cycles will obviously disturb fertility. With therapy, the menstrual cycles return to their regular pattern for the individual. In summary, thyrotoxicosis occurring in prepubertal girls may result in slightly delayed menarche. In adult women, the effects of thyrotoxicosis on the reproductive system are seen on the hypothalamic–pituitary axis with alterations in gonadotropin release and also in the circulating levels of SHBG, which alter steroid metabolism or biologic activity. These effects produce the variable clinical picture seen in women with thyrotoxicosis.

Hyperthyroidism and physical development
Children born with neonatal Graves’ disease have no defects in the reproductive system that can be related to this disease. Physical development is normal, however, and skeletal growth is often accelerated without a modification of final height. The delay in puberty may be related to the impact of thyrotoxicosis on body composition (i.e., decreased percentage of body fat), which is thought to be related to the onset of puberty and menarche. Rarely, thyrotoxicosis may occur in children in association with polyostotic fibrous dysplasia, cafe au lait pigmentation, and precocious puberty (McCune-Albright syndrome). Precosity has been described in one-third of the affected girls; and large, unilateral follicular cysts may be present and presumably are responsible for the sexual precocity of the gonadotropin-independent type. Thyrotoxicosis results from single or multiple thyroid adenomas.

Hyperthyroidism and menstrual cycle
Thyrotoxicosis occurring before puberty has been reported to delay sexual maturation and the onset of menses, although Saxena did note that, in thyrotoxic girls, the mean age of menarche was slightly advanced over that of their control population without endocrine disease. The association of thyrotoxicosis and precocity in this disorder appears to be coincidental. Although ovulatory menstrual cycles occur in women with thyrotoxicosis, menstrual disturbances are common. Therefore, the possibility of pregnancy should be considered in an amenorrheic thyrotoxic woman. This is important because many of these women may receive treatment with radioactive iodine, which is contraindicated in pregnancy. Oligomenorrhea is the most common abnormality, and it may progress to amenorrhea, first described in the classic study by von Basedow. Polymenorrhea is distinctly less frequent, in comparison to its occurrence in hypothyroidism. The frequency of these menstrual disorders varies in different series. Benson and Dailey found that out of 221 hyperthyroid patients 58% had oligomenorrhea or amenorrhea and 5% polymenorrhea. This is in general agreement with other older studies such as those of Goldsmith et al. More recently, in India Joshi et al. found menstrual irregularities in 64.7% of hyperthyroid women, compared to 17.2% of healthy controls. These irregularities sometimes preceded thyroid dysfunction. However, Krassas et al. found irregular cycles in only 21.5% out of 214 thyrotoxic patients. These discrepant results may be attributed to either genetic and other factors or to more delayed diagnosis in India than in Greece. The weight loss and psychologic disturbances (primarily anxiety) seen in thyrotoxicosis may also contribute to sexual dysfunction. Thyrotoxic women frequently present with increased LH, FSH, and estrogen levels; and the gonadotropin response to gonadotropin releasing hormone (GnRH) is increased, although the mid-cycle LH peak may be reduced or absent.

Hypothyroidism and the female reproductive system
Production of SHBG is decreased in hypothyroidism. As a result, serum estradiol and testosterone concentrations are reduced, although free levels of these hormones remain normal. The metabolism of both androgens and estrogens is also altered in hypothyroidism. Androgen secretion is decreased, and the metabolic transformation of testosterone shifts toward androstenedione rather than androsterone, the reverse of that seen in hyperthyroidism. With respect to estradiol and estrone, hypothyroidism favors metabolism of these steroids via 16α-hydroxylation over 2-oxygenation, resulting in increased formation of estriol at the expense of 2-hydroxyestrone and its derivative, 2-methohyestrone. The alterations in steroid metabolism disappear when the euthyroid state is restored. Serum FSH and LH values are usually normal, but the midcycle FSH and LH surge may be blunted or absent. In postmenopausal women, serum FSH and LH concentrations may be somewhat lower than expected, and the response to GnRH may be reduced. The anovulation is reflected in the frequent finding of aproliferative endometrium on endometrial biopsy. TRα-1 and TRβ-1 receptors have been found in follicular fluid. Earlier work indicated that thyroxine enhanced the action of gonadotropins on luteinization and progestin secretion by cultured granulosa cells, and it has been recently noted that in a group of infertile women, those with elevated TSH levels had a higher incidence of out-of-phase biopsies than women with normal TSH. The defects in hemostasis reported in hypothyroidism, such as decreased levels of factors VII, VIII, IX, and XI, may also contribute to the pathogenesis of polymenorrhea. Ovulation and conception can occur in mild hypothyroidism, but in the past those pregnancies that did occur were often associated with abortions in the first trimester, stillbirths, or prematurity. Recent studies indicate these events may be less common but that gestational hypertension occurs often in pregnant women with untreated hypothyroidism. Pregnancy occurring in women with myxedema has been reported to be uncommon, but this is somewhat hard to document and may be the result of anovulation. The use of L-thyroxine is not helpful in treating euthyroid patients for infertility, menstrual irregularity, or the premenstrual syndrome. Some myxedematous women will present with amenorrhea and galactorrhea and elevated serum prolactin concentrations. Thus, thyroid evaluation should be an essential part of the work-up in any person with galactorrhea. If hypothyroidism is the cause, the amenorrhea and galactorrhea and elevated serum prolactin will disappear promptly with thyroxine therapy. There is an increased incidence of Hashimoto’s thyroiditis in individuals with Turner’s syndrome, and, although a chromosomal linkage between autoimmune disease and the X chromosome has been suggested, this has not been confirmed. Inherited abnormalities in serum TBG are X-linked, and patients with Turner’s syndrome may have low serum TBG values. Women with hypothyroidism have decreased metabolic clearance rates of androstenedione and estrone and increased peripheral aromatization. The ratio of 5α/5β metabolites of androgens is decreased in hypothyroid women, and there is an increase in the excretion of estriol and a decrease in the excretion of 2-hydroxyestrone and its derivative 2-methoxyestrone.

Hypothyroidism and physical development
The reproductive tract appears to develop normally in cretins; thus, hypothyroidism during fetal life does not appear to affect the normal development of the reproductive tract. Hypothyroidism in prepubertal years generally leads to short stature and may lead to a delay in sexual maturity.

Hypothyroidism and the menstrual cycle
An interesting syndrome described by Kendle and Van Wyk and Grumbach occurs not infrequently: it is characterized by precocious menstruation, galactorrhea, and sella enlargement in girls with juvenile hypothyroidism. The cause is thought to be an overlap in the pituitary production of TSH and gonadotropins, with the latter causing early ovarian secretion of estrogens and subsequent endometrial stimulation with vaginal bleeding. Prolactin levels are elevated, leading to galactorrhea. The estrogen and progesterone response of the ovary to human chorionic gonadotropin is increased, possibly from prolactin induction of ovarian LH receptors. In this way hyperprolactinemia may sensitize the ovaries to the low circulating gonadotropin levels present prepubertally. However, there is no pubertal increase in the adrenal production of androgen precursors, so that axillary and pubic hair are usually not apparent. Therapy with thyroxine in proper dosage results in prompt alleviation of the symptoms. In adult women, hypothyroidism results in changes in cycle length and amount of bleeding and has been reported in association with the ovarian hyperstimulation syndrome.108 In an Indian study, 68.2% of hypothyroid women had menstrual abnormalities, compared to 12.2% of healthy controls. Menorrhagia is a frequent complaint and is probably due to estrogen breakthrough bleeding secondary to anovulation, which is frequent in severe hypothyroidism. Some investigators have reported a high incidence of thyroid hypofunction in women with premenstrual syndrome. Most of the thyroid disease was subclinical hypothyroidism, defined as an augmented response of TSH to TRH. Many of the affected women were reported to have complete relief of premenstrual syndrome (PMS) symptoms with L-T4 therapy.

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