Stuart R. Gallant, MD, PhD

Steroid hormone replacement therapy (HRT) is a topic that has been in the scientific and popular press a lot recently.  Your primary care physician has a wealth of information about the benefits and risks of HRT.  Also, tucked between the cryotherapy spas, high-end golf cart dealers, and discount jewelry outlets at your local upscale mall, you may find what have become to be known as “hormone restoration centers.”  They make broad claims to reduce fat, increase muscle tone, increase libido, improve sleep, reduce prescription drug use, and lower risk of illness.  However, at least some of these claims may not be supported by scientific evidence, and these services may not be covered by medical insurance.

In the first part of this two-part post, we looked at the pharmacology of androgens (male hormones) and estrogens (female hormones).  In the second part of this two-part post, we look at steroid hormone replacement therapy—its potential benefits and its risks.

General Health For Men and Women

Before talking about steroid hormone supplementation in men and women, it is important to discuss general health.  Ideally, everyone would eat a balanced diet, get 7 to 9 hours of restful sleep, and exercise regularly.

For several reasons, it is important to consider general health prior to considering steroid hormone replacement:

1. Advice of primary care physician:  A thorough review of the patient’s general health by a skilled primary care physician—not merely the physician overseeing a hormone replacement clinic—is important to uncover undiagnosed medical conditions and review risk factors of steroid hormone replacement.
2. There are lower risk strategies to boost health:  Steroid hormones have powerful effects on the body, both positive and negative.  Prior to undertaking hormone supplementation, it may be worth reviewing lower risk approaches.  For example, if the goal is to preserve bone density, has the patient undertaken a regular exercise program?  Exercise offers some benefits of both testosterone and estrogen without the risks of HRT.
3. Significant obesity can affect hormone levels:  An extra 10 pounds has no measurable effect, but obesity on the order of 100 pounds can alter the levels of testosterone and estrogen in the body.  In a study of obese men undergoing gastric bypass surgery to promote weight loss, SHBG, total testosterone, and free testosterone all increased following the surgery with improvement continuing throughout the year-long study follow up [1].  In contrast to the reduced testosterone in obesity, obese women (and men) have elevated estrogen [2].

Testosterone Therapy

There is a modest decline in testosterone with age in men.  This decline has been documented in several medical studies [3]:

Because the fall off is only modest and may not cause any practical effect on any given older male patient, the current recommendations for hormone replacement in men to do support population-based screening and treatment based on falling below a certain testosterone threshold.  Instead, the approach to the patient is one that looks for one or more correctible conditions linked with low testosterone (for example, low libido or anemia).  In an individual with such a treatable condition and a low laboratory value for testosterone, treatment can be considered after discussing the risks and benefits with the patient.  The following table presents the benefits and risk in rank order with those supported by the strongest medical evidence at the top of the table [3]:

So clearly there is some potential benefit, but there is also some risk.  Each patient needs to weigh both in a discussion with his primary care physician.

Estrogen and Progesterone Therapy

A decline in estrogen and progesterone production is intimately tied to menopause which is a permanent end to a woman’s monthly cycle due to a cessation of ovulation.  The average levels of estradiol and estrone leading up to and following menopause, as well as the average levels of FSH and LH, are shown in the figure below [4]:

For American women, menopause occurs on average at the age of 51.  Two to eight years prior to menopause, the menstrual cycle may become irregular (perimenopause).  Women may experience menopause in a number of ways:

• Medical studies have associated menopause with:  hot flashes, night sweats, irregular bleeding, vaginal dryness, sleep disturbances.
• Other associations are possible but have not been proved in medical studies:  mood swings, depression, impaired memory or concentration, urinary incontinence, or sexual dysfunction.

Because these issues can relate to other medical conditions, a woman should discuss them with her physician to understand the cause and explore treatment.  In the year 2000, almost 40% of women 50 to 74 in the United States used hormone replacement therapy to blunt uncomfortable symptoms of menopause [3]; however, clinical trials under the title of Women’s Health Initiative (WHI) brought that practice into question.  More than 160,000 women aged 50 to 79 years were enrolled in the WHI.  Some significant risks of hormone replacement were uncovered by the study, leading to a decline in hormone replacement therapy, particularly among women who are some years separated from menopause.

Some of the events of concern within the WHI data were (risks shown in red, benefits in green):

The currently recommended approach to the topic of post-menopausal hormone replacement therapy is:

• Patient assessment:  confirm whether hot flashes or night sweats are adversely affecting sleep, functioning, or quality of life
• Risk assessment:  confirm that contraindications do not exist for patient (breast, endometrial or other estrogen dependent cancer; cardiovascular disease (heart attack, stroke, transient ischemic attack); acute liver disease; undiagnosed vaginal bleeding)
• Recommendations:
  • HRT Recommended If:  1) age < 60 yr, 2) menopause onset within 10 years, and 3) low risk of breast cancer and cardiovascular disease.
  • Consider HRT With Caution If:  1) age ≥ 60 yr, 2) menopause onset > 10 years prior, or 3) moderate risk of breast cancer and cardiovascular disease.
  • HRT Not Recommended IF:  high risk of breast cancer or cardiovascular disease
  • HRT Not Recommended IF:  1) age ≥ 60 yr, and 2) moderate risk of breast cancer and cardiovascular disease.
  • HRT Not Recommended IF:  1) menopause onset > 10 years prior, and 2) moderate risk of breast cancer and cardiovascular disease.

Some consideration to bear in mind:

• Consulting a primary care physician or gynecologist to review risks and benefits.
• For patients who have had hysterectomy, estrogen-alone treatment is an option.
• Other options exist for blunting some effects of menopause, including antidepressants (venlafaxine, fluoxetine, or paroxetine), gabapentin, pregabalin, clonidine, and therapies to reduce bone loss (bisphosphonates, and others).
• Non-systemic hormonal therapies can be helpful for genitourinary symptoms (intravaginal estrogen creams, tablets, rings; prasterone; and ospemifine).

Harrison’s Principles of Internal Medicine 21^st Edition provides reliable, peer-reviewed medical information about hormone replacement.  In addition, Stanczyk and co-authors offer a review of some of the practices that fall outside of evidence-supported medicine [5].  They point out that:

• “Plant-derived” products often begin with a plant source raw material which is then transformed chemically.  So, there is no reason to think of these products as more natural, and therefore safer.
• The use of topical progesterone products is supported by very few studies, and therefore subject to more uncertainty regarding efficacy, risk, and benefit.
• There are significant questions about the correlation of salivary and serum hormone levels, raising questions about the use of salivary hormone tests.
• Steroid products provided by custom compounding pharmacies vary significantly in potency, compared to regular prescription pharmaceuticals.

Conclusions

Each patient should recall that a regular relationship with a primary care physician is highly correlated with better health.  Any concern about personal health, including hormone levels, should be shared with a person’s doctor in order to receive the best evidence-based medical advice.

[1] Van de Velde, F., et al.  “Metabolism of testosterone during weight loss in men with obesity,” J Steroid Biochem Mol Biol, 209, 105851 (2021).

[2] Zumoff, B.  “Hormonal Abnormalities in Obesity,” Acta Med Scand, Suml. 723, 153-60 (2009).

[3] Loscalzo, J., et al.  Harrison’s Principles of Internal Medicine 21^st Edition, McGraw-Hill (2022).

[4] Rannevik, G., et al.  “A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density,” Maturitas, Volume 61, Pages 67-77 (2008).

[5] Stanczyk, F.Z., et al.  “Bioidentical hormones,” Climacteric 24, 38–45 (2021).

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