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Cited by 41Hormonal and reproductive studiesPharmacovigilance and Adverse Drug ReactionsHealthcare Regulation

Perspective: Regulatory Agencies' Changes to Testosterone Product Labeling

Corona, Giovanni, Maggi, Mario·2015·The Journal of Sexual Medicine
DOI 10.1111/jsm.12951
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Abstract

A biochemical decrease in circulating testosterone (total testosterone, TT ≤ 10.4 nMol/L or 300 ng/dL) is a relatively common condition, particularly in aging men. Data derived from a Florentine sub‐analysis of the European Male Aging Study indicate that, in this geographic area, 8% of the general population, aged 40 years or older, have the condition, although asymptomatic [1]. However, all the guideline recommendations of dedicated scientific societies suggest that the diagnosis of late‐onset hypogonadism (LOH) must be considered only in the presence of specific symptoms. It is well recognized that sexual dysfunctions are the most specific symptoms characterizing male hypogonadism (HG) during adulthood [2]. In a large series of subjects consulting an andrology unit for sexual dysfunction in Florence, overt HG was present in 20% of the entire cohort [1]. Hence, having sexual dysfunction appears to double the chance of having low testosterone (T). Currently, the question is whether it is safe for the sexual medicine clinician to prescribe T preparations for subjects with low T and specific symptoms. The answer is not easy, in particular considering recent claims on safety and on the reported increased risk of cardiovascular (CV) events associated with T use [3]. The Coordination Group for Mutual Recognition and Decentralised Procedures‐Human (CMDh), a regulatory body representing European Member States—after a review by the European Medicines Association (EMA)'s Pharmacovigilance Risk Assessment Committee (PRAC)—has agreed by consensus that there is no consistent evidence of an increased risk of heart problems with T medicines in HG men (http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Testosterone‐containing_medicines/human_referral_prac_000037.jsp&mid=WC0b01ac05805c516f). PRAC also noted that the lack of T itself could increase the risk of heart problems. However, the use of T in healthy older men is not an authorized use in the European Union (EU, http://www.ema.europa.eu). A few months after the EMA's PRAC position statement, the cognate U.S. agency, the Food and Drug Administration (FDA), released an opposite opinion for a possible elevated CV risk associated with starting or continuing T therapy (http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm). The FDA cautions that prescribing T products is approved only for men who have low T levels caused by certain medical conditions. In particular, only subjects with primary or secondary HG (sHG) resulting from problems within the testis, pituitary, or hypothalamus (e.g. genetic problems, or damage from surgery, chemotherapy, or infection) should be treated. In contrast, the FDA emphasized that the benefits and safety of T medications have not been established for the treatment of low T levels due to aging, even if a man's symptoms seem related to low T. In other words, only hypogonadal men with a well‐defined etiological condition must be systematically treated, but not those with an age‐related T decrease. Table 1 shows the main causes of HG (i.e. ≤10.4 nMol/L or 300 ng/dL) in a large series of men consulting for sexual dysfunction in Florence (n = 4220), categorized according to LH levels [4]. Only in one half of the cases of primary HG can an etiological condition be identified. Klinefelter syndrome accounts for the majority of testicular disorders. The figure is even more impressive when sHG is considered. In this case, a causal condition can be inferred only in 10% of the subjects. This is particularly interesting, because, as stated before, sHG is by far the most prevalent form of LOH. Therefore, according to FDA criteria, more than 85% of the symptomatic subjects with low T consulting for sexual dysfunction should not be treated, because the T decline is “age‐related” and therefore treatment would put patients at risk for cardiac or other major adverse CV events (MACE). Is this indication evidence based? We recently published a meta‐analysis restricted to T placebo‐controlled randomized controlled trials (RCTs) on different primary outcomes because studies with T and specific CV endpoints as the primary outcome were few and of short duration [6]. Our systematic review did not substantiate the view that T treatment brings with it any additional risk of CV‐related adverse events, when HG is properly diagnosed and replacement therapy correctly performed. When a separate analysis was performed according to the baseline population characteristics, similar results were obtained even in studies enrolling subjects with an age‐related condition [6]. Recently, results from the TSAT study have been reported [7]. This is a multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, 16‐week trial on T supplementation in 596 adult, hypogonadal men with decreased energy or decreased sexual drive [7]. By combining the results from this study with those from the aforementioned meta‐analysis on RCTs performed after excluding tho

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  • Only 50% of primary hypogonadism and 10% of secondary hypogonadism show an organic origin for testosterone deficiency.

    “Only 50% and 10% of primary and secondary HG, respectively, show an organic origin for the TD.”

    From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [17]

  • The large majority of secondary functional hypogonadism is associated with unhealthy metabolic conditions such as metabolic syndrome, diabetes, and obesity.

    “In particular, the large majority of secondary functional HG is associated with unhealthy metabolic conditions, such as MetS, diabetes, and obesity [17].”

    From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [17]

  • The large majority of subjects consulting for sexual dysfunction and having low testosterone can be categorized as functional hypogonadism (85%), with secondary hypogonadism prevalent over primary at a ratio of 5.5:1.

    “In addition, it should be emphasized that the large majority of subjects consulting for sexual dysfunction and having low T can be categorized as functional HG (85%), with secondary HG the prevalent form, with a ratio of 5.5:1 vs. primary HG [17].”

    From Treatment of Functional Hypogonadism Besides Pharmacological Substitution (2020) · cites this paper as [17]

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Authors
Corona, G., & Maggi, M.
Affiliations
  • Azienda USL di Bologna (IT)
  • University of Florence (IT)
Corresponding author
Maggi, Mario
ORCID
Venue
The Journal of Sexual Medicine
Publisher
Oxford University Press (OUP)
Published
2015-08-01
Volume
12
Issue
8
Pages
1690-1693
ISSN
  • 1743-6095 (ISSN-L)
  • 1743-6109
DOI
10.1111/jsm.12951
OpenAlex
W2151492933
Cited by
41
References
9
Citations by year
2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 4 · 2018: 9 · 2017: 5 · 2016: 8 · 2015: 1
FWCI
6.67
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • The Journal of Sexual Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Florence Research (University of Florence) (submittedVersion)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Health Sciences › Health Professions › Health Information Management › Healthcare Regulation
Keywords
testosterone replacement therapy, cardiovascular risk, andropause, male hypogonadism, sexual dysfunction, regulatory agencies, FDA, EMA, pharmacovigilance, drug safety, prescribing restrictions, older men, United States, andrology

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