The Natural History of Endocrine Function and Spermatogenesis in Klinefelter Syndrome: What the Data Show

More knowledge about the development of the androgenic and spermatogenic compartments of the Klinefelter testis is needed to formulate a rational approach to fertility optimization and preservation in these men.

Robert Davis Oates, M.D.

Volume 98, Issue 2, Pages 266-273, August 2012

Efforts are underway to try and increase identification of Klinefelter males as soon as possible to allow intervention at an earlier stage, although it is unknown if that will necessarily change the course of the disorder. While this may certainly turn out to be important for the learning difficulties that are part of the Klinefelter phenotype, it is unclear at this time whether early therapeutic involvement in terms of androgen replacement or fertility is helpful or hurtful to the individual. This contribution will briefly summarize what is understood about testicular function and anatomy as regards both the androgenic and spermatogenic compartments.

  • Bob Oates

    In response to an email to me about the discussion a clinician was
    having with a young Klinefelter male and his parents and what to do
    vis-a-vis testosterone therapy and whether it should or should not be
    prescribed: “Thanks for the kind words. I think the concept of having a
    group of articles on the same topic is a great one and it was really
    educational to read all of them at the same time. So, difficult
    decisions for each individual patient and I certainly do not have all of
    the answers but it is fun to debate back and forth and what I like
    about the articles by Darius Paduch and the one by myself is that we can
    look at the same problem from completely opposite directions. On the
    issue of concentration/cognition – my feelings are that whatever
    learning difficulties the teenage Klinefelter patient has are not at
    all related to his testosterone levels (and “testosterone deficiency”.
    Here is my line of reasoning. 1. We know that the learning
    difficulties become manifest in the early school years when no male
    (46,XY or 47,XXY) has any testosterone floating around – they are all
    prepubertal in the second grade, for example, but the learning
    difficulties in the 47,XXY patient can be recognized already. 2. If
    testosterone levels were at all directly related to cognition, then why
    are females intellectually as capable as males? They are because, in my
    view, testosterone is not related to cognition in this context. 3 Males
    with hypogonadotropic hypogonadism syndromes, for example Kallmann
    Syndrome, have much lower (if any) testosterone values as they enter and
    progress through the early teenage years until they are diagnosed and
    treated but they have no intellectual disability/compromise. 4 . The
    more X chromosomes (3 or 4), the greater the degree of intellectual
    impairment. The only connection I think that exists is in those who are
    not progressing through puberty (actually a small percentage of
    Klinefelter males) and so feel out of place at school and are doing
    poorly at school for that reason – to stimulate virilization may improve
    their self esteem and they perform better – not due to an improvement
    in brain cognitive ability but due to improvement in self esteem.
    Anyway, that is my reasoning against the thought that giving
    testosterone will improve cognitive ability and concentration in
    Klinefelter teenagers who are virilizing – as they almost all do. On
    the issue of libido (I know a different subject but one that I think is
    illustrative of our “testosterone-centric US Urologist mindset”), if you
    ask Urologists the question, “What is it that sets up the brain to have
    libido during embryonic and fetal development and what drives libido as
    an adult” – the vast majority would immediately and emphatically say
    “TESTOSTERONE”. So, here is the question for them, “If that is true
    then how is it that phenotypic females with complete androgen
    insensitivity have normal libido – their tissues (brain and otherwise)
    have never and will never have any response to circulating
    androgens/testosterone”. Interesting thought. Anyway, I just think we
    all need to be cautious in our use of testosterone for Klinefelter males
    and others.

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