Table 17.1 in Braverman & Cooper’s 2013 chapter in Werner & Ingbar’s The Thyroid textbook, 10th edition, lists many causes of thyrotoxicosis.
One of the interesting causes of thyrotoxicosis, rarely mentioned in public discourse, is “Circulating HCG or Mutant TSHR [TSH receptor] hypersensitive to HCG.”
What is HCG?
“Human chorionic gonadotropin” is a hormone produced by the placenta after implantation.
HCG is used to detect pregnancy status in some pregnancy tests.
This non-TSH hormone can stimulate a thyroid gland like TSH and TSHR antibodies do. Therefore, as they stimulate a healthy thyroid, they elevate thyroid hormones. A side effect is sometimes the suppression of TSH.
NORMAL PREGNANCY VERSUS THYROTOXICOSIS
The following draws mainly on Moleti et al, 2019 “Hyperthyroidism in the pregnant woman.”
In a normal pregnancy, HCG stimulates the thyroid gland, and the rise in thyroid hormones naturally reflects a drop in TSH.
The TSH falls below reference range in 10-15% of healthy pregnancies, according to this source (statistics vary).
But is the low TSH a sign of “excess” Free T4 and Free T3? Not necessarily, even if sometimes T4 is above reference.
Excess is relative to the body, and pregnancy is a special case. This is why guidelines have proposed trimester-specific reference ranges to prevent doctors from being alarmed.
The lower TSH and higher thyroid hormone levels are not necessarily harmful during pregnancy. But when TSH drops very low in those 10-15% of women, further tests are usually done to confirm whether a person has Graves’ antibodies and how high thyroid levels truly are.
HCG, which stimulates the thyroid even when TSH is suppressed, can raise hormone levels enough to cause “Gestational transient thyrotoxicosis” (GTT) in the first trimester (peaking at 8-11 weeks) in 1-5% of pregnancies.
Therefore, normal pregnancy with a low TSH (up to 15% of women) might be benign because the body normally has a lot of Total T4, but thyrotoxicosis may exist in a smaller minority (up to 5% of women) who have excess Free T4.
GTT is more likely to occur in twin or multiple pregnancies. Rarely, when a person has a mutant TSHR receptor, it makes the receptor hypersensitive to normal levels of HCG. (Moleti et al, 2019)
Hmmm, TSHR receptors can mutate? They can become hypersensitive? They can be activated by things other than TSH molecules? Mind blowing.
We can learn a lot about the uncertain relationships between TSH, the TSH receptors, and thyroid hormones by looking at pregnancy.
MORNING SICKNESS AND REVERSE T3
In extreme cases of “Gestational transient thyrotoxicosis” (GTT), HCG-stimulated hyperthyroidism can cause “Hyperemesis gravidarum” (HG).
In this HG syndrome, the mother experiences an extreme version of morning sickness — continual vomiting, weight loss, and dehydration.
These certainly sound like some of the symptoms of thyrotoxicosis in Graves’ disease.
However, while TSH and Graves’ disease antibodies tend to enhance T3 secretion more than T4 from the thyroid gland (they increase the T3:T4 ratio), HCG enhances T4 secretion more than T3 (lowering the T3:T4 ratio), enabling doctors to distinguish between GTT and Graves’ autoimmune hyperthyroidism.
In hyperthyroid HG patients who are ill and losing weight, their higher T4 levels lead to much higher levels of Reverse T3.
RT3 increased in HG by an average of 31% higher than healthy pregnant controls in a study by Juras et al, 1983.
Because GTT and even its more severe form HG usually fade by the beginning of the second trimester, it is rarely treated except with fluids and electrolytes and a short course of propranolol (beta-blocker) to reduce hyperemesis and thyrotoxicosis.
HCG BEYOND PREGNANCY
HCG is not only secreted in pregnancy, but also after bilateral oophorectomy, during perimenopause and menopause. (Cole et al, 2009)
In women past menopause, the HCG is secreted from the pituitary gland along with the LH/FSH horomone, which is structurally similar to HCG and to TSH.
What? The pituitary gland can secrete HCG? Weird.
What is a pituitary gland doing secreting a hormone the body makes in early pregnancy? This is not pregnancy, this is menopause. Weird.
Again, we learn that the female body during transitions in fertility simply does weird things to pituitary TSH and TSH-like hormones.
Tell me again why we trust TSH so much?
If HCG enters TSH receptors, then it could interfere with the TSH ultrashort feedback loop, as I’ve described in previous posts … It could lower the TSH independently of thyroid- hormone-caused TSH suppression.
However, in non-pregnant women, the HGC appears in blood at much lower levels than pregnant women, and the molecules are only half as potent in stimulating the TSH receptors on the thyroid gland (Basham and Bryan, 2017).
The pituitary-secreted HCG might not lead to thyrotoxicosis, but it could result in strange thyroid hormone and TSH laboratory results.
Theoretically, if HCG can interfere with the TSH-TSHR feedback loop, a thyroidless woman on a static dose of thyroid hormone may see TSH mildly oversuppressed without her thyroid hormones elevating.
PUZZLING ASPECTS OF HCG-DRIVEN THYROID FUNCTION
The role of HCG in pregnancy continues to puzzle researchers, as explained by Scott Forbes in 2014.
Questions abound: Why does the human body secrete HCG to drive T4 levels higher in early pregnancy? What causes severe morning sickness — HCG, or too much Reverse T3, or something else? Is the morning sickness actually a good sign of thyroid health and iodine sufficiency?
Let’s start with theories about why HCG secretion stimulates the thyroid gland more than TSH in early pregnancy.
HCG BACKUP IN CASE OF IODINE DEFICIENCY
Some have theorized that in pregnancy HCG serves as a backup system for TSH or at least complements it.
Others have suggested that the fetus and mother are engaging in a struggle over thyroid hormone supply. The developing embryo secretes HCG to say “I want more thyroid hormone” which may be necessary in cases of iodine deficiency. Iodine was far more deficient throughout most of human history.
When iodine is deficient, the gland can’t synthesize thyroid hormone molecules. We need need 3 iodine atoms to make a T3 molecule, and 4 iodine atoms to make a T4 molecule.
Without HCG, a person’s thyroid gland will oversecrete T3 as T4 drops, and TSH will rise to overstimulate the gland. The excess T3 production keeps the person healthy while the T4 drops, until the body doesn’t have enough raw material to maintain T3 supply.
In a pregnant woman in the first trimester, help comes to the baby in the form of the HCG hormone, since its role is to increase T4 (to rebalance the T3:T4 ratio in iodine deficiency) and to lower the TSH.
THE RUNAWAY TRAIN OF HCG STIMULATION
However, a strange thing happens — there is no way to stop this runaway train when the gland is healthy and there’s enough iodine supply.
Nothing tells HGC to stop when mom and baby have enough thyroid stimulation.
While HCG will not reduce in response to rising thyroid hormone levels in the mother, neither will it decrease when the fetus has enough. The result may be thyrotoxicosis for the fetus as well.
HCG is not subject to the mother’s HPT axis for control of thyroid hormone supply, and it may be forced from the mother at her expense.
The excess hormone supply in those with healthy thyroids and those with enough iodine supply is also puzzling to many people, because it can be so pathological.
REVERSE T3 AS CAUSE OR BYPRODUCT?
In a normal pregnancy, the mother secretes a lot of excess bound T4 thyroid hormone.
The enzyme that inactivates thyroid hormones (Deiodinase Type 3) to Reverse T3 and T2 is normally highly expressed in the tissues of the placenta, where it serves to protect the fetus from excess thyroid hormone … but it can only do so much when thyroid hormone levels become too high.
Forbes theorized that it is not the severe morning sickness that elevates RT3, but the other way around.
Forbes suspected that the excess Reverse T3 and/or T2 produced in the mother’s blood supply may cause the extreme morning sickness symptoms in hypermimesis gravidarium (HG).
While T4 and T3 levels continue to increase in the second half of pregnancy, Reverse T3 levels fall sharply. Morning sickness disappears.
This correlation raises the hypothesis that unless HCG itself is the direct trigger of mom’s illness, Reverse T3 and/or T2 may indeed be the cause of, or at least byproducts strongly associated with, of morning sickness illness in the first trimester.
HCG-INDUCED ILLNESS INDICATES THYROID HORMONE HEALTH?
In Forbes’ theory, the effects of HCG-thyroidal stimulation have a silver lining — they reveal the mother’s thyroid health status even while she suffers for it.
When iodine is not deficient and the gland is healthy, she is more likely to result in vomiting and hyperemesis gravidarum, because the T4 is higher and more T4 converts to RT3.
Conversely, when signs of morning sickness are entirely absent, it’s nice for the mother, BUT it may indicate the mother’s thyroid gland and/or thyroid hormone supply is compromised.
As additional proof for this theory, Forbes points out research proving that among mothers who do NOT experience morning sickness associated with HCG, miscarriage is a higher risk.
Miscarriage together with a lack of morning sickness are also more common in regions of the world with iodine deficiency.
Miscarriage and lack of morning sickness are also both more common in mothers who are over the age of 30, an age when hypothyroidism becomes more common.
Any doctor who treats a female patient during pregnancy of menopause and sees the distinctive T3/T4 ratio of thyroid hormones elevating and symptoms developing should understand HCG’s temporary phase of oversecretion and its distinction from Graves’ disease.
In addition, doctors should be aware that a _lack_ of morning sickness and a higher TSH during pregnancy could be an indicator of thyroid dysfunction, iodine deficiency, or thyroid hormone underdose.
Basham, M. M., & Bryan, T. (2017). Postmenopausal pregnancy? Evaluation of elevated hCG in a 59-year-old woman. Case Reports, 2017, bcr-2016-218807. https://doi.org/10.1136/bcr-2016-218807
Braverman, L. E., & Cooper, D. S. (2013). Introduction to thyrotoxicosis. In L. E. Braverman & D. S. Cooper (Eds.), Werner & Ingbar’s the thyroid: a fundamental and clinical text (10th ed..). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins Health.
Cole, L. A., Khanlian, S. A., & Muller, C. Y. (2009). Normal production of human chorionic gonadotropin in perimenopausal and menopausal women and after oophorectomy. International Journal of Gynecological Cancer: Official Journal of the International Gynecological Cancer Society, 19(9), 1556–1559.
Forbes, S. (2014). Pregnancy sickness and parent-offspring conflict over thyroid function. Journal of Theoretical Biology, 355, 61–67. https://doi.org/10.1016/j.jtbi.2014.03.041
Juras, N., Banovac, K., & Sekso, M. (1983). Increased serum reverse triiodothyronine in patients with hyperemesis gravidarum. Acta Endocrinologica, 102(2), 284–287.
Moleti, M., Di Mauro, M., Sturniolo, G., Russo, M., & Vermiglio, F. (2019). Hyperthyroidism in the pregnant woman: Maternal and fetal aspects. Journal of Clinical & Translational Endocrinology, 16, 100190. https://doi.org/10.1016/j.jcte.2019.100190