Advances in antiretroviral therapy (ART) have made it possible for persons with human immunodeficiency virus (HIV) to have a lifespan that approaches that of people without HIV without progressing to AIDS or transmitting HIV to sexual partners or infants. There is, therefore, increasing emphasis on maintaining health throughout the lifespan. To receive optimal medical care and achieve desired outcomes, persons with HIV must be consistently engaged in care and able to access uninterrupted treatment, including ART. Comprehensive, evidence-based HIV primary care guidance is, therefore, more important than ever. Creating a patient-centered, stigma-free care environment is essential for care engagement. Barriers to care must be decreased at the societal, health system, clinic, and individual levels. As the population ages and noncommunicable diseases arise, providing comprehensive healthcare for persons with HIV becomes increasingly complex, including management of multiple comorbidities and the associated challenges of polypharmacy while also attending to HIV-specific health concerns. Clinicians must address issues specific to preventive health, including cancer screening, providing recommended vaccinations, and promoting sexual health, including sexually transmitted infection diagnosis, treatment, and prevention. Clinicians also must address issues for specific populations, including persons of child bearing potential during preconception and pregnancy, children, adolescents, and transgender and gender-diverse individuals. This guidance from an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America updates the previous 2020 HIV Primary Care Guidance.
* If total testosterone is used for initial testing, a determination of sex hormone–binding globulin and/or free testosterone is strongly recommended when alterations of binding proteins are suspected (including patients with cirrhosis and hepatitis, hyper or hypothyroidism, or nephrotic syndrome). Free testosterone may be determined by equilibrium dialysis (most reliable but most expensive) or using the free online testosterone calculator developed by the Hormonology Department, University Hospital of Ghent, Belgium [121]. So-called direct free testosterone (analogue) assays are unreliable and should not be used.
Table.4.
Tests That May Be Performed Under Certain Circumstances
Recommendations
• In general, routine testosterone testing is not recommended among cisgender males with HIV. However, morning serum testosterone levels are recommended in adult cisgender men with decreased libido, erectile dysfunction, reduced bone mineral density (BMD) or low trauma fractures, hot flashes, or sweats.
• Obtaining testosterone levels in cisgender women at baseline in non-research settings is not recommended.
Recommendations
Cisgender men with HIV, especially those with advanced disease, are at risk for hypogonadism. Interpretation of testosterone values must be made in clinical context, as all currently available assays (including measures of total, free, and bioavailable testosterone) are associated with technical issues that may result in significant variability. Testing should be performed on a specimen obtained in the morning (ideally before 10 AM) andc onfirmed with repeat testing if the result is below the lower limit of normal. Recommendations differ regarding the optimal assay to use for initial testing in the setting of HIV. Testosterone circulates primarily bound to plasma proteins (including sex hormone–binding globulin and albumin). If total testosterone is used for initial testing, a determination of sex hormone–binding globulin and/or free testosterone is stronglyr ecommended when alterations of binding proteins are suspected (including patients with cirrhosis and hepatitis, hyper or hypothyroidism, or nephrotic syndrome). Free testosterone may be determined by equilibrium dialysis (most reliable but most expensive) or using the free online testosterone calculator developed by the Hormonology Department, University Hospital of Ghent, Belgium [121]. So-called direct free testosterone (analogue) assays are unreliable and should not be used. If a diagnosis of hypogonadism is established, measurement of luteinizing hormone and follicle-stimulating hormonem is recommended to determine whether the source of dysfunction is primary (testicular) or central (pituitary or hypothalamic) in origin. Hypogonadism should be treated by clinicians who are familiar with monitoring patients on androgen replacement therapy (see Section 4). For recommendations pertaining to age-appropriate cancer screening, see Section 5
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The prevalence of hypogonadism among cisgender men with HIV has been reported to be high prior to the introduction of ART. However, screening for hypogonadism is recommended only for men who have symptoms [317, 318]. In 2014, the FDA released safety alerts that warned of potential increased cardiac risk associated with testosterone replacement products [319–321]. Subsequently, a large systematic review and meta analysis failed to demonstrate an increased risk of cardiac events in the general population; however, caution remains [322]. Although the Endocrine Society Guidelines [323] recommend short-term testosterone replacement therapy (TRT) for cisgender men with HIV and low testosterone, many patients have remained on TRT long term. It is unclear whether those who were diagnosed with hypogonadism at the time of their HIV diagnosis need to remain on TRT after immune recovery on ART. Since the FDA advisory, the overall percentage of cisgender men who use TRT has declined, but less so among those with HIV [324, 325]. As the population of men with HIV ages, clinicians should balance the benefits against the harms of continuing TRT that may no longer be indicated. TRT may result in testicular atrophy and permanent inability to produce the natural hormone. Men may experience “withdrawal” when TRT is stopped, given the steroidal effects of testosterone as well. Therefore, initial TRT should be prescribed with caution and only in cisgender men with symptomatic hypogonadism, given the long-term side effects.
WHAT PROGRESS HAS CDC MADE WITH STANDARDIZING TOTAL TESTOSTERONE AND ESTRADIOL TESTS?
Since HoSt began in 2010, CDC has had more than 350 participants in 15 countries. Participants have shown measurable improvements for both total testosterone (TT) and estradiol (E2). Specifically, the among-laboratory bias has decreased from 16.5% in 2007 to 2.8% in 2017 for TT and from 54.8% in 2012 to 13.9% in 2017 for E2. Not only has bias improved, but data...
Clinical Utility and Analytical Aspects of Direct Measurements of Free Hormones Using Mass Spectrometry-Based Methods (2022) Mark M. Kushnir, Heather A. Nelson, and Kelly Doyle
Background
The free hormone (FH) hypothesis states that hormone action and the corresponding biological effects are mediated by the unbound (free) fraction of hormone in circulation. The in vivo relationship between protein-bound and FH is complex and dynamic. In most individuals, measurement of total hormone (TH) is usually...
* Ensuring the accuracy of serum testosterone level is vital for diagnosing hypogonadism across diverse clinical settings. However, numerous challenges arise, such as inconsistencies in laboratory standardization, reference range variations, and the expenses linked with top-tier equipment. Additionally, technical and logistical obstacles further complicate assay procedures. This chapter aims to explore the diverse array of testosterone assays and their interpretation to provide clarity in clinical practice.
Testosterone plays a pivotal role in regulating various...
* The data from the present analyses suggest that the interaction of the three sex hormones with their cognate binding proteins is highly complex and dynamic and influenced by their relative circulating concentrations. Therefore, models of testosterones binding to SHBG, based on the assumption of fixed apparent binding affinity of sex hormones with SHBG, that do not consider the influence of estradiol and dihydrotestosterone on the free testosterone fraction are unlikely to provide accurate estimates of free testosterone fraction.
* Because of these complex interactions between various sex hormones as well as other ligands with sex hormone binding globulin, direct measurements of free testosterone using a reliable assay, such as the equilibrium dialysis method, may be a superior marker of testosterone’s treatment effect.
The thread discusses the modulation of circulating free testosterone fraction during Testosterone Replacement Therapy (TRT) and its relationship with other hormones. Here are the main points from the discussion:
Free Testosterone Fraction:
The thread emphasizes the importance of the free testosterone fraction, which is the biologically active form of testosterone.
It explains that total testosterone levels alone may not provide a complete picture of hormonal status.
Hormone Interactions:
The discussion highlights the complex interplay between...
* Collectively, these data highlight the non-linear, concentration-dependent modulation of testosterone repartitioning into bound and free fractions by each of the three sex hormones.
*Our finding that the estradiol, DHT, and testosterone interact to alter free testosterone fraction non-linearly suggests that in men with hypogonadism who are receiving TRT, free testosterone levels should be measured using a reliable method to guide the dose titration. The models that do not consider changes in estradiol and DHT concentrations are susceptible to error in estimating free testosterone concentrations.
*These data suggest that changes in estradiol and dihydrotestosterone concentrations should be considered in evaluating response to testosterone treatment because of their differential influence on free testosterone concentrations in addition to their ability to exert other independent biologic effects. Because of these complex interactions between various sex hormones as well as other ligands with sex hormone binding globulin, direct measurements of free testosterone using a reliable assay, such as the equilibrium dialysis method, may be a superior marker of testosterone’s treatment effect.
