Prescribing sex hormones: A pragmatic primer for 2023

Why is prescribing sex hormones so difficult? Whether it be HRT for hot flashes or testosterone for lagging libido, prescribing hormones is not “rocket science.” Yet it remains contentious, challenging and often under-prescribed by many physicians. Why? Let’s explore the murky world of sex hormonal therapies and find out what’s behind this mistrust and confusion. Where do we start? Let’s define what we are talking about. A hormone is a chemical that is made by specialist cells, usually within an endocrine gland, and is released into the bloodstream to send a message to another part of the body. The three major types of hormones are protein, steroid and amine. Sex hormones are of the steroidal variety and include androgen, estrogen and progestogens. Generally speaking, sex hormones play an essential role in reproduction and sexual development. They are responsible for: puberty and sexual development, reproduction, sexual desire, regulating bone and muscle growth, inflammatory responses, regulating lipid levels, promoting hair growth and body fat distribution. The concentrations of these hormones vary throughout an individual’s lifetime and are influenced by several factors, including age, menstrual cycle, menopause, stress, medications and recreational drug use. While we could talk about contraception, endometriosis or androgen deprivation in metastatic prostate cancer, I would like to focus on three main hormone prescriptions in primary care. Let’s do a deeper dive into the murky waters of HRT in menopausal women, testosterone deficiency in men and hormonal transition in the gender diverse. Fanning the flames: menopausal hormonal therapy (MHT) Menopause occurs at an average age of 51 years. By definition, a woman is in menopause when she has not had a period for 12 consecutive months (in the absence of other causes). As well, 85% of women report symptoms of varying type and severity and in approximately 20% of women, these are severe. Symptoms include anxiety, moodiness, sleep difficulties, weight changes, headaches, vasomotor instability (hot flushes and night sweats), palpitations, hirsutism, decreased libido and dyspareunia to name but a few of a very long list. Despite the universality of menopause in a woman’s reproductive life and the high frequency of bothersome symptoms, this diagnosis remains undertreated in many women. A 2021 U.S. study estimated this number to be 73% of women between the ages of 45 to 65. The reasons for under-prescribing can be spelled out by three letters, WHI (Women’s Health Initiative). This research, published 2002 to 2006, concluded that combined estrogen and progesterone therapies increased the risks of heart disease, stroke and venous thromboembolism and invasive breast cancer. Despite this research being criticized for the use of out-of-date hormonal preparations, too elderly age cohorts and misleading statistical analysis, this study did major damage to this therapeutic area and these negative repercussions have remained decades later for both practitioners as well as the public. There are countless up-to-date guidelines (e.g., SOGC, NAMS, endocrine societies) and practical algorithms that exist to help guide therapy and a multitude of products and delivery systems for taking hormones. Most agree that within the first 10 years of menopause (generally women 50 to 59 years old) the risk of blood clots and stroke is extremely low, and the risk of breast cancer is not increased if exposure to hormones is five years or less). If the uterus is intact, both estrogen and progesterone are needed, post hysterectomy, estrogen alone will suffice. Menopausal hormonal therapy remains the most effective therapy for vasomotor symptoms and vaginal symptoms. If I don’t venture down the rabbit hole of bio-identical hormones, this is straightforward, right? Summary: Diagnostic difficulty: low / perceived low to moderate Therapeutic difficulty: low / perceived moderate Therapeutic risks: low to moderate / perceived high MHT is a grossly underutilized effective therapy for symptomatic menopausal females The mighty T: testosterone replacement therapy (TRT) for testosterone deficiency (TD) Unlike menopause, not every man gets a low testosterone level that is symptomatic, formerly known as “andropause.” To further confuse the issue, many men get a wide variety of symptoms that sound remarkably like low testosterone with testosterone levels that are “normal.” Here lie some of the challenges of trying to prescribe hormones for what is best described as testosterone deficiency. I personally preferred the older term “testosterone deficiency syndrome.” Do we only treat men who are low in absolute terms (calculated bioavailable testosterone under 4.0) or men with testosterone on the lower end of a normal range? That, of course, can be referenced at several cut points depending on whether it is a Canadian versus U.S. authority versus any number of “expert sites” usually financed by companies making testosterone boosters/supplements. Serial testing and more elaborate endocrine investigations are generally crucial to confirming diagnosis and ensuring a primary or secondary hypogonadism. With lower testosterone numbers, there is so much more range and controversy regarding who should be treated. There is also an element of abuse potential and concerns, particularly with insistent younger men essentially demanding TRT for better workouts and recovery, more energy and muscle mass. As this is a sex hormone, the biggest gains are in this realm, i.e., the improvement of low libido and sexual function, as well as general well-being, and improved quality of life (QOL). The number of therapeutic options has dwindled significantly over the years and are further threatened by frequent drug shortages. While experts have debunked any concern regarding TRT causing prostate cancer, we still need a definitive study on cardiovascular risk. Most clinical “problems” with TRT are related to supra-physiologic dosing (e.g., erythrocytosis, high estrogen levels). There are excellent Canadian guidelines that are up-to-date from 2021 and have everything most practitioners need to manage most patients. Managing men without a confirmed diagnosis can be very frustrating. Treat symptomatic men with confirmed hypogonadism and the gains are remarkable. Summary: Diagnostic difficulty: moderate / perceived high Therapeutic difficulty: low / perceived moderate Therapeutic risks: low to moderate / perceived moderate to high TD is diagnosable, treatable and TRT improves QOL Give and take: cross-sex hormones for medical transition (masculinizing / feminizing) If we struggle with the hormone replacement of aging men and women, medical transition in the gender diverse population can be the most challenging of all. Each step from diagnosis to treatment to followup can feel monumental even though it is surprisingly straightforward medical care in most adult patients. The diagnosis of gender dysphoria is crucial and is made by reviewing DSM criteria. An informed consent model is the platform on which we move forward with medical transition, whether this be hormones, surgery or both. The key is learning all the options available for feminizing (anti-androgen, estrogen, +/- prometrium) and masculinizing (testosterone) and then understanding the degree/aggressiveness to which the patient wishes to transition: Is this a more traditional binary transition or a more subtle non-binary stance? Side-effects, risks, followup care all must be learned, and there can be a steep learning curve to start. Patients are generally self-motivated and well-read when it comes to transition options, so we don’t have to spend a lot of time sussing out information for them. The “Sherbourne Guidelines” is an excellent comprehensive Canadian document, and WPATH SOC 8 is the recently updated international “bible” on the subject. Most endocrine societies have very elaborate clinical practice guidelines. This area of medicine has come a long way, and a lack of resources can no longer be used as an excuse not to safely prescribe and follow up patients on transitional hormonal therapies. Summary: Diagnostic difficulty: low / perceived moderate to high Therapeutic difficulty: moderate / perceived moderate to high Therapeutic risks: low / perceived moderate to high Gender dysphoria can be easily diagnosed and successfully treated with medical transition This high-level primer touches on some key ideas to consider when prescribing sex hormones. It’s not for the faint of heart. You don’t have to be an endocrinologist (urologist, gynecologist, psychiatrist) to get started. Patients who choose to venture down these winding therapeutic paths can be rewarded with remarkably improved QOL, and physicians may find this challenging work immensely gratifying. Dr. Ted Jablonski is a writer who has retired his family practice to focus on sexual medicine and transgender health in Southern Alberta.

Prescribing sex hormones: A pragmatic primer for 2023

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