Thyroid Replacement Therapy for Hypothyroidism

thyroid examination
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Hypothyroidism (under-active thyroid) is a serious medical condition that can significantly impact your health. In addition to frequently causing many troublesome symptoms (including weight gain, hair and skin changes, constipation or diarrhea, infertility, fatigue, and aches and pains), hypothyroidism can also produce serious medical problems involving the heart and lungs, the gastrointestinal system, the nervous system, the eyes, and the muscles.

In addition, it can cause various metabolic changes including hyponatremia (low serum sodium concentration), elevated cholesterol levels, and increases in serum creatinine (a measure of kidney function). Severe hypothyroidism can even cause cognitive changes, coma, and death.

If you have hypothyroidism, it is important for you and your doctor to adequately treat the condition in order to relieve your symptoms, and to mitigate and prevent these various medical problems.

What Are the Goals of Treatment?

The goals in treating hypothyroidism are quite simple. They are:

  • to normalize thyroid hormone levels (specifically, T4, T3 and TSH levels)
  • to eliminate symptoms of hypothyroidism
  • to halt and reverse any effects hypothyroidism may be having on various organ systems
  • if a goiter is present (as is sometimes the case with Hashimoto’s disease, for instance), to reduce its size

How Is Treatment Accomplished?

On paper, the treatment of hypothyroidism is pretty straightforward.

It is treated by prescribing an oral thyroid hormone preparation (usually levothyroxine, sold as Synthroid, a T4 preparation), of a dosage that is sufficient to restore normal thyroid hormone levels, without producing toxicity from too much thyroid hormone. 

However, in practice the optimal treatment of hypothyroidism has generated a fair amount of controversy.

The main controversies are twofold: 

  • How low should you push the TSH levels before you consider hypothyroidism to be adequately treated? 
  • Is taking T4 alone sufficient, or should T3 also be prescribed? 

(To help keep the thyroid hormones straight, read a quick review of the thyroid gland, T4, T3, and TSH.)

We will consider both of these controversies after we first have a look at “standard” therapy for hypothyroidism.

The 'Standard' Treatment of Hypothyroidism

Endocrinologists (specialists in hormonal disorders) almost universally recommend treating hypothyroidism with T4 alone. In young, healthy people doctors will generally begin with what is estimated to be a “full replacement dose” of T4 (that is, a dose that is supposed to completely restore thyroid function to normal). The full replacement dose is estimated according to body weight, approximately 1.6 mcg per kg. For most people this will be between 50 and 200 mcg per day. 

In older people or people with coronary artery disease, the initiation of thyroid replacement therapy is usually done more gradually; beginning with 25-50 mcg daily, and increasing the dosage over time.

People should take T4 on an empty stomach, otherwise the absorption of the medication will be erratic.

Usually, doctors recommend taking the medication first thing in the morning, then waiting at least an hour to eat breakfast (or even to drink coffee). Taking the medication at bedtime, several hours after the last meal, also appears to work, and may be a more convenient approach for many people. Read more about the timing of taking thyroid medication.

TSH levels are monitored to help optimize the dose of T4. TSH—thyroid stimulating hormone—is produced in the pituitary gland in response to thyroid hormone levels. So, when thyroid hormone levels are low (as in hypothyroidism), TSH levels respond by increasing, in an attempt to “whip” more thyroid hormone out of the thyroid gland.

When hypothyroidism is adequately treated, TSH levels typically drop back down into the normal range. So, a mainstay in determining the best dose of T4 is to measure TSH levels.

While symptoms of hypothyroidism usually begin to resolve within two weeks of initiating treatment, it takes about six weeks for TSH levels to stabilize. So, TSH levels generally are measured six weeks after treatment is begun. If TSH levels remain above the target range, the dose of T4 is increased by 12-25 mcg per day, and TSH levels are repeated after six more weeks. This process is continued until the TSH level reaches the desired range, and symptoms are resolved. Once the optimal dose of T4 is settled upon, TSH levels are measured every year or so thereafter, to make sure the treatment remains optimized. 

There are different formulations of T4 made by different manufacturers. While all FDA-approved formulations are judged to be suitable, most experts recommend sticking to the same formulation, and not switching, since the dosage equivalents may vary somewhat among different preparations.

This, then, is the standard approach to treating hypothyroidism, and again, it is pretty straightforward. It appears to work for most people; that is, this treatment method results in the resolution of symptoms and the restoration of normal thyroid hormone levels in most people with hypothyroidism.

But not in all. And this is where the controversies come in.

Controversy: What Is the Appropriate Target for TSH?

As we have seen, measuring TSH levels is a mainstay in assessing the adequacy of thyroid replacement therapy. 

But not everyone agrees what a “normal range” is for TSH levels. Most major endocrine societies consider the normal range to be between 0.5-4.5 (or even 5.0) mIU/L. However, a large dissenting group (the American Association of Clinical Endocrinologists) has stated that the top range of normal should be reduced to 3.0 mIU/L. People whose TSH levels are higher than that upper limit, they have said, may actually be hypothyroid.

This question is important for several reasons, but (as we have seen) one of them is that, when treating hypothyroidism, it is important to know whether the TSH level while on therapy is in the normal range, or not. If your treated TSH level is 4.2 mIU/L, according to the majority of endocrinologists you are adequately treated; but according to an important minority you need a higher dose of thyroid hormone. 

So, this ongoing controversy can often complicate the treatment of hypothyroidism.

Controversy: Is T4 Alone Adequate or Should T3 Be Given?

T4 is the major circulating thyroid hormone, but it is not the active hormone. T4 is converted to T3 in the tissues, as needed. And T3 is the thyroid hormone that does all the work. (T4 is “merely” a prohormone—a repository of potential T3, a way of making sure enough T3 can be created on a minute-to-minute basis as it is needed.)

When we give T4 and not T3, we are “trusting” the tissues of the person with hypothyroidism to convert just the right amount of T4 to T3, at just the right place, and at just the right time. (In fact, this is a chief rationale endocrinologists use for giving T4 alone—the body “knows” best when and where it needs T3, and as long as you supply it with enough T4 it will do the job right. When doctors give T3 in addition to T4, they are “second guessing” the body’s own physiology.)

However, a substantial amount of evidence has been developed suggesting that, at least in some people with hypothyroidism, that efficient conversion of T4 to T3 is lacking. In other words, despite the fact that their T4 levels may be normal, their T3 levels may be low—especially in the tissues, where T3 actually does its work. 

Why T4 to T3 conversion may be abnormal in some people is, at this point, largely speculation—although at least one group of patients has been identified with a genetic variant (in the diodinase 2 gene) that reduces the conversion of T4 to T3. In any case, it appears that doctors should be treating at least some people who have hypothyroidism with both T4 and T3. 

Giving appropriate doses of T3 is trickier than appropriately dosing T4. T4 is inactive; if you give too much there is no immediate, direct tissue effect (since it has to be converted to T3 before the tissues are affected). T3 is a different story; it is the active thyroid hormone, so if you give too much, you can produce hyperthyroid effects directly—a risk, for instance, to people with cardiac disease. 

When adding T3 to T4 during thyroid replacement therapy, most experts recommend administering a ratio of T4:T3 of between 13:1 to 16:1, which is the ratio that exists in people without thyroid disease. This is a higher proportion of T4:T3 than has been used in most randomized clinical trials.

Randomized trials comparing outcomes with T4 alone to T4+T3 generally have not shown significant benefit in the use of combination therapy in populations of patients with hypothyroidism. However, these trials were not designed to account for the probability that the benefits of combination therapy are likely to be limited to a certain subset of people with hypothyroidism. And despite the lack of strong clinical trial evidence, virtually all experts now agree that there are indeed certain people with hypothyroidism who ought to receive both T4 and T3.

Treating Hypothyroidism: A Reasonable Approach

Given what we know about hypothyroidism, TSH levels, and the relationship between T4 and T3, for most experts a reasonable approach to the treatment of this condition looks like this:

Start with the “standard” approach, using T4 medication only, carefully assessing both TSH levels and the level of symptom relief, and adjusting the dosage of T4 accordingly. For most people, this approach will work well.

If symptoms of hypothyroidism persist despite achieving TSH levels in the high-normal range (that is, above 3 mIU/L but below 5.0 mIU/L), then either or both of two alternative approaches should be considered:

1) Increase the dose of T4 sufficiently to push the TSH level to below 3 mIU/L.

2) Add T3 to the treatment regimen, with appropriate precautions.

Before choosing alternative 2, many experts recommend measuring serum T3 levels, and documenting that they remain near the low end of the normal reference range, or below. If T3 levels are in the mid-to-high normal range, it is very doubtful that adding T3 to the treatment regimen will improve things. (Read more about measuring thyroid hormone function.)

So: If you are being treated for hypothyroidism using the “standard” approach and your symptoms have not been substantially mitigated, you need to talk to your doctor about considering one or both of these alternative approaches.

A Word From Verywell

The treatment of hypothyroidism is indeed pretty straightforward, at least in theory. And in most people with this condition, the straightforward, “standard” approach to therapy works quite well.

But if the standard approach has not relieved your symptoms of hypothyroidism, it is time to consider a “non-standard,” alternative approach—either pushing TSH levels further down within the normal range, or adding T3, or both.


Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, et al. REVIEW: Treatment of Hypothyroidism With Combinations of Levothyroxine Plus Liothyronine. J Clin Endocrinol Metab 2005; 90:4946.

Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 2014; 24:1670.

Panicker V, Saravanan P, Vaidya B, et al. Common Variation in the DIO2 Gene Predicts Baseline Psychological Well-being and Response to Combination Thyroxine Plus Triiodothyronine Therapy in Hypothyroid patients. J Clin Endocrinol Metab 2009; 94:1623.