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Update in Andrology

Department of Andrology, Concord Hospital, ANZAC Research Institute and University of Sydney, Sydney, New South Wales 2139, Australia

Address all correspondence and requests for reprints to: Professor D. J. Handelsman, ANZAC Research Institute, Sydney, New South Wales 2139, Australia. E-mail: djh{at}anzac.edu.au.

	Abstract

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Context: This is an invited review based on a presentation at the 2007 Annual Scientific Meeting of The Endocrine Society.

Objective: The objective of the review was to highlight a selection of the most important peer-reviewed papers in andrology published over the last 1–2 yr.

Evidence Acquisition: This was a comprehensive survey of all papers published in major endocrinology journals over the last 2 yr augmented by personal knowledge and literature searching as well as an e-mail survey of more than 40 leading andrologists.

Evidence Synthesis: From the list of suggested papers, the findings of a short list considered the most important were reviewed, aiming to focus on findings that influence thinking and practice in the field of andrology.

Conclusions: Important advances highlighted included establishing genetic paternity for men with Klinefelter’s syndrome as a realistic therapeutic option via testicular sperm aspiration coupled with intracytoplasmic sperm injection in vitro fertilization, using population registry linkage data to define the natural history of Klinefelter’s syndrome in the community and identifying active cellular uptake mechanisms for SHBG-bound testosterone challenging the quasiaxiomatic status of the free hormone hypothesis. Other important recent contributions reviewed are on testosterone effects on the prostate, hormonal male contraception, possible temporal trends in blood testosterone concentrations in American men, and The Endocrine Society’s position papers on testosterone assays and guidelines on testosterone prescribing.

	Introduction

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THIS UPDATE REVIEWS progress in andrology as reflected by peer-reviewed papers published over the last 1–2 yr. Adopting a framework of seeking new or improved clinical or scientific practice that evolves in a continuum of concepts, verification, and practice, it aims to understand how particular papers contribute to what we think, what we talk about, and ultimately what we do as endocrinologists.

Andrology is defined as male reproductive health, medicine, and biology and has strong roots in endocrinology. Androgens dictate not only masculine development but also are major determinants of the gender dichotomous features of human physiology and pathology either directly or indirectly via lifestyle and behavioral mechanisms. A pivotal fact necessitating more andrology research is the gender gap in life expectancy, which remains 5–7 yr shorter for men, compared with their female partners in all affluent societies. This gap has not narrowed over the last century as life expectancy increased dramatically. It now corresponds to a population deficit of approximately 4.5 million mainly older American men who died prematurely, compared with their female partners. Given men’s poorer mortality and morbidity outcomes, the publication of a special issue on men’s health in the Journal of the American Medical Association in November 2006 was an important recognition of how men’s health had been the overlooked background in medical research.

A survey of leading andrologists inquiring about the most influential peer-reviewed journal article over the last 1–2 yr identified a wide range of suggestions including the following: discovery of micro-RNA; testosterone and the metabolic syndrome; hormonally active chemicals in the environment; testosterone and prostate disease; secular trends of decline in blood testosterone concentrations; ageing men’s fertility and sperm; genetics of idiopathic hypogonadotropic hypogonadism and delayed puberty; production of germ cells from stem cells; recovery of sperm output after hormonal male contraception; fertility in Klinefelter’s syndrome (KS); development of oral selective androgen receptor modulator (SARM); and megalin, SHBG, and the free hormone hypothesis. Surprising omissions were androgens and cardiovascular disease (still the most frequent cause of male deaths); the impact of marketing-driven and unproven androgen overuse among middle-aged and older men; and the pitfalls of T assays.

	Important Papers

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The following seminal papers reported important novel findings or conclusions whose impact on clinical or scientific practice remains tentative, subject to replication and/or interpretation.

Testosterone and the prostate

In the JAMA Men’s Health Special Issue of November 2006, Marks et al. (67) reported a study of 44 middle-aged and older men (aged 44–78 yr) with nonspecific symptoms associated with late-onset hypogonadism (a new synonym for andropause) according to the Aging Male Syndrome (AMS) questionnaire together with a low blood testosterone less than 10.4 nmol/liter (300 ng/dl). These features are consistent with the 2006 U.S. Endocrine Society andropause guidelines as warranting testosterone treatment (1). Eligible men recruited from a single general urology practice were randomized into treatment with a subreplacement dose of short-acting injectable testosterone enanthate (150 mg every 2 wk) or a saline placebo. Prostate biopsies performed before and after 6 months treatment showed no consistent change in intraprostatic testosterone (T) or dihydrotestosterone (DHT) concentrations (or in prostate volume or histology or lower urinary tract symptoms) despite the expected effects of the exogenous T treatment on standard androgen-sensitive measures (increased blood T, DHT, prostate-specific antigen PSA, estradiol, hemoglobin, and decreased blood LH). This provides limited reassurance for use of exogenous T in this older male population because such modest, subreplacement doses avoid excessive intraprostatic androgen concentrations. However, the interpretation of these findings for risk of subsequent prostate cancer remains uncertain because the relationship, if any, between maintaining normal intraprostatic androgens and risk of subsequent prostate cancer is not defined. A limitation of this study design, substituting a saline injection for oil vehicle placebo because sterile injectable oil is difficult to obtain, is adequate for objective end points such as hormone concentrations. However, it is not effective masking for subjective end points such symptoms or effort-dependent measures such as muscle strength and function so that interpretation of symptomatic responses from this study would be difficult.

Hormonal male contraception

In the field of male contraception, Liu et al. (2) collated nearly all (90%) the primary data from 30 hormonal male contraceptive studies involving 1549 men older than 15 yr in a comprehensive integrated analysis showing that such regimens were fully reversible. Although the last four decades saw the marketing of reliable and reversible female hormonal contraceptives, arguably the greatest contribution of applied science in the 20th century in freeing women to participate more fully in society beyond the home, no new male contraceptive methods were introduced in the last century. This shifted the burden of effective family planning further onto women, leaving men only mechanical methods that are either not reliable or reversible enough for modern family life. Rebalancing this so men share more equitably the burdens as well as the benefits requires new male contraceptive methods that are both reliable and reversible. Hormonal methods are the closest to implementation with the favored approach of a depot androgen/progestin combination showing promisingly high reliability (3). In this context, using sperm concentrations as a well-proven surrogate measure for fertility in male contraceptive studies, Liu et al. (2) demonstrated convincingly that the other pillar requirement, reversibility, is now well established for hormonal male contraceptive regimens. This work, a collaboration of all active investigators in the field who meet annually, reflects the ongoing public sector collaboration comprising academic investigators working with governmental (CONRAD, National Institutes of Health) and nongovernmental (World Health Organization, Population Council) agencies that has driven all major advances in the field, notably the landmark proof of principle clinical trials and, most recently, in developing the regulatory framework required for registration of such novel products (4).

Regrettably, commercial product development has stalled because the priorities of the private sector dictate that these opportunities will languish, whereas pharmaceutical companies neglect the manifest public and medical demand. This market failure of product development, which means that no hormonal male contraceptives are in regular clinical usage anywhere, makes questionable the value of the recently updated Cochrane analysis, restricted to analyzing studies using candidate or prototype regimens and a surrogate (sperm suppression) rather than a marketed products and clinical (contraceptive failure) end points that Cochrane reviews usually require (5). Product development using the now well-proven approaches will require genuine entrepreneurial efforts by other pharmaceutical companies or leadership from the emerging pharmaceutical industries of rapidly developing countries in which the paralysis by me-too pseudoinnovation and corporate mergers and acquisitions may be less overwhelming.

Secular changes in blood T concentrations

An important, thought-provoking paper from the seminal Massachusetts Male Aging Study (6) analyzed the now well established age-specific decline in blood T concentrations across the three cross-sectional waves of that long-running cohort that retains more than 500 of the original 1700 men over 15 yr of follow-up. Travison et al. (6) demonstrated a temporal decrease in blood T concentrations above and beyond the age-specific decline in blood T concentrations. This appeared to be independent of the effects of obesity; chronic disease; and all other measured demographic, health, and lifestyle covariables. Although this unequivocal secular change is progressive in time, it is of relatively small magnitude and is spread unevenly across waves and ages (Fig. 1), whereas the biological significance of such an effect remains moot (7). Such age-period-cohort observations are notoriously difficult to disentangle. If the observations are biological rather than methodological, they could be attributable to any unmeasured health or environmental effects demonstrating a contemporaneous secular trend over the same period. Attributing such relatively small residual effects to other unmeasured factors is risky because it assumes that the impact of all larger effects (e.g. obesity) are fully accounted for by the statistical model including nonlinearity or interactions of covariables. Furthermore, artifactual changes in T measurements cannot be fully excluded because the nonextraction commercial T immunoassay used is vulnerable to drift over decades due to unavoidable changes in antibody supply and specificity, detection methods, and long-term sample storage.

View larger version (16K): [in this window] [in a new window]   FIG. 1. Crude mean total T concentrations by Massachusetts Male Aging Study study wave (T1, T2, T3) with confidence bands (dotted lines). [Reproduced with permission from Travison et al.: Journal of Clinical Endocrinology & Metabolism 92:44–45, 2007 (6 ). © The Endocrine Society.]

The dilemma of interpreting the data of Travison et al. (6) highlights the value of The Endocrine Society’s position paper on blood T assays (8). This provides a comprehensive and thoughtful review of the present state of T assays, a field of rampant confusion and pitfalls. Whereas the paper’s conclusion is uncontestable that improved laboratory performance proficiency was important, the paper was too hesitant in not recommending a more definitive solution, a switch to a chemical, mass spectrometric (MS) for assay for steroids and related small molecules. The Endocrine Society has understandable historical pride and attachment to steroid immunoassays, reflecting the Nobel prize-winning work of Berson and Yalow that, together with pioneering efforts of other society members, revolutionized endocrinology by introducing an entirely new dimension in sensitive measurement of hormones. Evidence is, however, mounting that the use-by date for steroid immunoassays is imminent because the limitations of immunoassay no longer meet the increasing demands on precision for T assays. It is striking that for sports doping, when disqualification of a professional athlete’s living was at stake, steroid immunoassays were never accepted as having sufficient specificity for proof of steroid identity. At the same time, MS assays are becoming more widely available, with the larger contract research laboratories and the society’s peer-reviewed journals leading the way, and it is time to accelerate their uptake into routine clinical practice. Whereas MS traditionally lost out in sensitivity to immunoassay, this could be overcome by larger samples, whereas immunoassays could never fully overcome their lack of specificity relative to MS. Now with technological development of ultrasensitive MS capable of matching immunoassay sensitivity to couple with their unrivaled specificity, it is time for a paradigmatic switch from immunoassays to MS-based steroid measurements. At the same time, performance proficiency remains of fundamental importance for every assay laboratory.

Guidelines for T therapy of androgen-deficient men

During the last year, The Endocrine Society promulgated guidelines on T prescribing for men with androgen deficiency (1) that largely mirror analogous international (9) and previous Australian national guidelines (10) (Table 1). Despite such weak evidence for efficacy of T treatment for andropause that the Institute of Medicine could not recommend a definitive Women’s Health Initiative-style randomized, controlled trial (11), testosterone prescribing has risen 15- to 20-fold in the United States but not Europe, Asia, or Australia (12). Restraining wishful expectations, commercial exploitation, and recreational or cosmetic hormone use by the worried, wealthy well remains a difficult task. The lack of systematic evidence to support such T usage (1) seems at odds with the strength of some recommendations. Guidelines that tacitly accept the blurring of the fundamental distinction between male aging and disease-based androgen deficiency due to hypothalamo-pituitary or testicular pathology are unlikely to restrain excessive, unproven T usage (12). This emphasizes the difficulty in producing prudent and effective clinical guidelines in the vacuum of reliable evidence.

	Highlighted Major Papers

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Major contributions highlighted in this update are papers advancing practical management (14) and understanding the wide spectrum of clinical features and natural history of KS (15, 16, 17, 18, 19) as well as an important cell biology study that provides an important challenge to prevailing dogma in understanding steroid hormone transport and uptake into cells (20).

Paternity in KS

Since the first description of KS by Harry Klinefelter, a fellow of Fuller Albright, in 1942 (21) and the subsequent identification of its chromosomal basis in 1959 (22), KS has been a textbook archetype of life-long hypogonadism (23). The clinical features of KS, the most frequent cause of azoospermia or androgen deficiency, provide a complete spectrum of male reproductive health and its diverse disorders. Key features of its natural history include irreversible, untreatable sterility excluding genetic paternity so that fertility management was restricted to bypassing male infertility by using donor sperm or adoption. The sterility of KS is due to the high prevalence of azoospermia, present in 92% of KS men able to provide a semen sample with the remainder having a median of 0.1 million sperm/ml (24). This severe spermatogenic defect results from progressive germ cell death after migration to the primordial aneuploid testis with a mass extinction (rather than the usual proliferation) during puberty and is described in an excellent recent review highlighting the challenge of this striking but unexplained biological phenomenon (25).

In a major advance on the natural history of KS, the bleak paternity prognosis has been conquered by application of modern reproductive technology. Using testicular sperm extraction (TESE) coupled with intracytoplasmic sperm injection, the first birth from testicular sperm from a father with nonmosaic KS (26) was described in 1998, a result confirmed by experienced in vitro fertilization clinics in small case series. Most recently using microsurgical TESE the same group reported a remarkable approximately 70% yield of viable sperm per procedure so that approximately 70% of KS men were able to father a child (14). In that retrospective analysis of 453 consecutive microsurgical TESE procedures over 8 yr, a single microsurgeon (P.N.S.) obtained sperm in 29 of 42 of KS men (69%) from among 39 of 54 successful microsurgical TESE procedures (72%). Once sperm were obtained, the fertilization and pregnancy outcomes were similar to other TESE/intracytoplasmic sperm injection procedures. This achievement substantially changes the expectations for KS men so that even with macroscopic TESE, rather than microsurgery, which allows identification of thicker tubules bearing scattered pockets of residual spermatogenesis, a realistic prognosis for paternity can now be provided. Nevertheless, with conventional macroscopic TESE, approximately 30% of KS men may be able to father children, although the procedures remain demanding and expensive and offer uncertain outcome for individuals. New management issues, the problems of success, now arise. One is whether the yield from micro-TESE can be improved sufficiently so that sperm will be so reliably obtained that unfrozen sperm can be used with concurrent in vitro fertilization or whether frozen sperm are needed to avoid risk of canceled in vitro fertilization cycles. Another crucial issue is whether prior T treatment, required to rectify lifelong androgen deficiency, has deleterious effects on spermatogenesis, thereby reducing chances of TESE sperm pickup. A series of ad hoc treatments used empirically by Schiff et al. (14) are logical, and further careful observational evidence is now urgently required in this area in which controlled trial data will be difficult to acquire for such rare situations. An important corollary for management of adolescent with KS is that, wherever possible, semen analysis should be obtained to facilitate opportunistic sperm cryostorage if azoospermia is not yet established to avoid need for future TESE. This important study marks an important change in the prognosis for paternity in KS, which must now be regarded as a plausible, if still not routine, expectation.

Natural history in KS: mortality and morbidity

The textbook description of the natural history of KS was acquired over decades by the gradual accumulation of astute clinical observations of disease associations in individual men or small case series. Whereas well-understood hormonal mechanisms may reinforce the validity of such linkages, in which such a connection is lacking, coincidental or artifactual associations are difficult to exclude. Even relatively large population-based cohorts, however, may have insufficient power to evaluate the significant associations for a rare disease like KS. In a tour de force, a recent series of observational studies from Denmark (15, 16, 17) and the United Kingdom (18, 19) provide the first solid framework describing the diverse clinical features and natural history of KS at a population level. These studies used data registry linkage methods that rely on the existence of an unique personal identifier code for each individual, which is also used in population-based registries for deaths, cancers, hospitalizations, or surgery using the standard international International Classification of Diseases coding for diagnosis. These requirements are most readily met by national health systems which mandate reliable recording of disease diagnosis and outcomes. A key feature of KS that makes such data linkage feasible is the standardized diagnosis by karyotyping performed by specialized cytogenetic laboratories (all five in Denmark, 25 of 27 in the United Kingdom participating) in which these are linked to other databases. The Danish and U.K. population registry studies differ mainly in the more sensitive matching of the Danish studies, using 5:1 controls matched for month and year of birth using a Cox model regression. By contrast, the U.K. studies used less sensitive national outcome rates as comparator, but this was partly overcome by the much larger national population (60 vs. 5.5 million). Key findings from these studies constitute a comprehensive clinical description of lifetime androgen deficiency in producing a diverse range of serious morbidity and mortality.

As a genetic disease with essentially normal life expectancy, KS provides a convenient population tracer for linked conditions, such as azoospermia and androgen deficiency, analogous to isotope dilution, capture-recapture, or drug tracer methodologies. Using the well-defined population prevalence of KS (156 per 100,000) from extensive birth surveys (Table 2), if KS comprises 1:3 cases of classical androgen deficiency or 1:10 cases of azoospermia, the population prevalence of these conditions can be estimated as approximately 0.5% and approximately 1.6%, respectively. Similarly, the Danish study showed KS was markedly underdiagnosed with less than 10% of cases identified by puberty and less than 20% ever diagnosed during life. Because the ubiquitous feature of tiny testes (<4 ml) in KS men would not be missed on any genital examination, the remarkable underdiagnosis is most likely attributable to the fact that most men never undergo genital examination by a doctor during their lives. This casts a striking spotlight on the neglect of male reproductive health even in well-organized, affluent health systems.

The strengths of population data registry linkage studies include the ability to provide a rapid, powerful, comprehensive, and cost-effective picture of lifelong health outcomes for a rare disease like KS. The limitations include the reliance on complete and accurate coding of outcomes (causes of death, cancers, disease, and hospitalization), having a registry-based diagnostic marker, and the inability to integrate additional individual biodata or ambulatory and nonregistry outcomes. These limitations leave scope for even larger cooperative data registry linkage studies as well as small, more intensive, well-controlled clinical trials. In concert, wider use of this population data registry linkage approach has the capacity to enlighten many areas of endocrinology.

Megalin, SHBG, and free hormone hypothesis

Hammes et al. (20) demonstrated the importance of megalin, a multiprotein uptake receptor from the conserved low-density lipoprotein receptor superfamily of endocytic receptors, to a protein-bound mechanism for sex steroid uptake into target cells. They combined cell biology experiments showing SHBG influences cellular uptake of sex steroids in vitro as well as megalin knockout mice to identify defects in sex steroid action in vivo. Although accompanied by a supportive editorial (27), the work attracted critical comments predominantly on the binding studies by Dr. W. Rosner (28), a distinguished Endocrine Society member and pioneer in the field of SHBG-bound sex steroid uptake mechanisms.

Using a wide range of in vitro techniques, it was shown that: 1) SHBG binds to megalin on either an immobilized chip or membrane receptors of cells expressing megalin, 2) SHBG binding was blocked by RAP (an endogenous megalin binding inhibitor) but not excess DHT, 3) tracer T uptake was blocked by RAP or SHBG excess, 4) megalin-mediated uptake of SHBG-bound DHT was replicated using fluorescein isothiocyanate-DHT, and 5) RAP-inhibitable uptake of tracer DHT bound to SHBG was similar to uptake of DHT bound to tracer SHBG. Rosner (28) criticized the specificity and quantitative aspects of tracer steroid uptake regarding the kinetics, metabolism, and potential for rapid recycling/reuptake of steroid as unresolved.

The in vivo studies examined sex steroid action in mice lacking functional megalin (29). The megalin knockout mouse has approximately 95% neonatal lethality due to widespread (lung, brain, kidney) maldevelopment, and the unexplained survival of a minority may influence interpretation of megalin function in them. In survivors, females exhibited failure of vaginal opening and males and nondescent of the left (but not right) testis. Supporting evidence for the claim of transient androgen resistance was that in fetal (but not mature) megalin knockout mice, T and DHT levels were increased, compared with controls, and that gene expression profiles in fetal gonads were consistent with impaired androgen action. The highly localized spatial and temporal manifestations in survivors that do not replicate fully either genetic or pharmacological androgen or estrogen receptor blockade is puzzling. Furthermore, mature mice have no circulating SHBG, although sex steroid insensitivity during mouse development remains plausible because the fetal liver secretes androgen-binding protein ABP, the mouse homolog of human hepatic SHBG.

These findings reinforce the work of Rosner and colleagues (30, 31) on the active role of SHBG-bound androgens in androgen action and question the validity of the free hormone hypothesis, which asserts that SHBG-bound T is a passive buffer for circulating free T. The sophisticated-sounding free hormone hypothesis, largely a product of outmoded 1970s pharmacological theory of drug interactions, has become a rarely challenged quasi-axiomatic belief in endocrinology. The free hormone hypothesis assumes unbound hormone is more readily diffusible into tissues and thereby bioactive. This overlooks the equal likelihood that such freely diffusible hormone is also more likely to undergo inactivating metabolism so that the net balance between bioactivity and inactivation remain impossible to determine by theory. It makes many other assumptions (binding equilibria are completed during capillary transit, all capillaries operate similarly, T binding affinity for SHBG is invariant). Empirically, the proliferation of calculational formulae for free or bioavailable T adds a further layer of inaccuracies adopting wrong stoichiometry, inaccurate SHBG binding affinity, and substitute an immunoassay for a SHBG binding assay, leading to limited validation and poor performance in large-scale usage (32).

The study by Hammes et al. (20) is a timely and important challenge to seek a more empirically valid basis for the physiological understanding of steroid transport and uptake into cells. Less axiomatic reliance on arbitrary and unreliable calculational devices to measure free or bioavailable T would allow a clearer understanding of androgen action, especially with regard to ageing whereby these derived T measures can confuse rather than enlighten.

	Footnotes

 
Disclosure Statement: There are no disclosures related to this work.

Abbreviations: DHT, Dihydrotestosterone; KS, Klinefelter’s syndrome; MS, mass spectrometric; T, testosterone; TESE, testicular sperm extraction.

Received June 26, 2007.

Accepted September 21, 2007.

	References

Top Abstract Introduction Important Papers Highlighted Major Papers References

 

1. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM 2006 Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 91:1995–2010[Abstract/Free Full Text]
2. Liu PY, Swerdloff RS, Christenson PD, Handelsman DJ, Wang C, Hormonal Male Contraception Summit Group 2006 Rate, extent and modifiers of spermatogenic recovery after hormonal male contraception: an integrated analysis. Lancet 367:1412–1420[CrossRef][Medline]
3. Turner L, Conway AJ, Jimenez M, Liu PY, Forbes E, McLachlan RI, Handelsman DJ 2003 Contraceptive efficacy of a depot progestin and androgen combination in men. J Clin Endocrinol Metab 88:4659–4667[Abstract/Free Full Text]
4. Aaltonen P, Amory JK, Anderson RA, Behre HM, Bialy G, Blithe D, Bone W, Bremner WJ, Colvard D, Cooper TG, Elliesen J, Gabelnick HL, Gu YQ, Handelsman DJ, Johansson EA, Kersemaekers W, Liu P, MacKay T, Matlin S, Mbizvo M, McLachlan RI, Meriggiola MC, Mletzko S, Mommers E, Muermans H, Nieschlag E, Odlind V, Page ST, Radlmaier A, Sitruk-Ware R, Swerdloff R, Wang C, Wu F, Zitzmann M 2007 10th Summit Meeting consensus: recommendations for regulatory approval for hormonal male contraception. J Androl 28:362–363[Free Full Text]
5. Grimes DA, Lopez LM, Gallo MF, Halpern V, Nanda K, Schulz KF 2007 Steroid hormones for contraception in men. Cochrane Database Syst Rev CD004316
6. Travison TG, Araujo AB, O’Donnell AB, Kupelian V, McKinlay JB 2007 A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab 92:196–202[Abstract/Free Full Text]
7. Bhasin S 2007 Secular decline in male reproductive function: Is manliness threatened? J Clin Endocrinol Metab 92:44–45[Free Full Text]
8. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H 2007 Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 92:405–413[Abstract/Free Full Text]
9. Nieschlag E, Swerdloff R, Behre HM, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morley JE, Schulman C, Wang C, Weidner W, Wu FC 2005 Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, and EAU recommendations. Int J Androl 28:125–127[CrossRef][Medline]
10. Conway AJ, Handelsman DJ, Lording DW, Stuckey B, Zajac JD 2000 Use, misuse and abuse of androgens: The Endocrine Society of Australia consensus guidelines for androgen prescribing. Med J Aust 172:220–224[Medline]
11. Liverman CT, Blazer DG, eds 2004 Testosterone and aging: clinical research directions. Washington, DC: Institute of Medicine, The National Academies Press
12. Handelsman DJ 2004 Trends and regional differences in testosterone prescribing in Australia: 1991–2001. Med J Aust 181:419–422[Medline]
13. Bliss M 2007 Harvey Cushing: a life in surgery. Oxford, UK: Oxford University Press
14. Schiff JD, Palermo GD, Veeck LL, Goldstein M, Rosenwaks Z, Schlegel PN 2005 Success of testicular sperm injection and intracytoplasmic sperm injection in men with Klinefelter syndrome. J Clin Endocrinol Metab 90:6263–6267[Abstract/Free Full Text]
15. Bojesen A, Juul S, Birkebaek NH, Gravholt CH 2006 Morbidity in Klinefelter syndrome; a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab 91:1254–1260[Abstract/Free Full Text]
16. Bojesen A, Juul S, Birkebaek N, Gravholt CH 2004 Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 89:3830–3834[Abstract/Free Full Text]
17. Bojesen A, Juul S, Gravholt CH 2003 Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study. J Clin Endocrinol Metab 88:622–626[Abstract/Free Full Text]
18. Swerdlow AJ, Higgins CD, Schoemaker MJ, Wright AF, Jacobs PA 2005 Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab 90:6516–6522[Abstract/Free Full Text]
19. Swerdlow AJ, Schoemaker MJ, Higgins CD, Wright AF, Jacobs PA 2005 Cancer incidence and mortality in men with Klinefelter syndrome: a cohort study. J Natl Cancer Inst 97:1204–1210[Abstract/Free Full Text]
20. Hammes A, Andreassen TK, Spoelgen R, Raila J, Hubner N, Schulz H, Metzger J, Schweigert FJ, Luppa PB, Nykjaer A, Willnow TE 2005 Role of endocytosis in cellular uptake of sex steroids. Cell 122:751–762[CrossRef][Medline]
21. Klinefelter HG, Reifenstein EC, Albright F 1942 Syndrome characterized by gynecomastia, apsermatogeensis without a Leydigism and increased excretion of follicle-stimulating hormone. J Clin Endocrinol Metab 2:615–627[Abstract/Free Full Text]
22. Jacobs PA, Strong JA 1959 A case of human intersexuality having a possible XXY sex-determining mechanism. Nature 183:302–303[CrossRef][Medline]
23. Handelsman DJ, Liu PY 2006 Klinefelters syndrome: a microcosm of male reproductive health. J Clin Endocrinol Metab 91:1220–1222[Free Full Text]
24. Lanfranco F, Kamischke A, Zitzmann M, Nieschlag E 2004 Klinefelter’s syndrome. Lancet 364:273–283[CrossRef][Medline]
25. Aksglaede L, Wikstrom AM, Rajpert-De Meyts E, Dunkel L, Skakkebaek NE, Juul A 2006 Natural history of seminiferous tubule degeneration in Klinefelter syndrome. Hum Reprod Update 12:39–48[Abstract/Free Full Text]
26. Palermo GD, Schlegel PN, Sills ES, Veeck LL, Zaninovic N, Menendez S, Rosenwaks Z 1998 Births after intracytoplasmic injection of sperm obtained by testicular extraction from men with nonmosaic Klinefelter’s syndrome. N Engl J Med 338:588–590[Free Full Text]
27. Adams JS 2005 "Bound" to work: the free hormone hypothesis revisited. Cell 122:647–649[CrossRef][Medline]
28. Rosner W 2006 Sex steroids and the free hormone hypothesis. Cell 124:455–457 (Letter)
29. Willnow TE, Hilpert J, Armstrong SA, Rohlmann A, Hammer RE, Burns DK, Herz J 1996 Defective forebrain development in mice lacking gp330/megalin. Proc Natl Acad Sci USA 93:8460–8464[Abstract/Free Full Text]
30. Kahn SM, Hryb DJ, Nakhla AM, Romas NA, Rosner W 2002 Sex hormone-binding globulin is synthesized in target cells. J Endocrinol 175:113–120[Abstract]
31. Rosner W, Hryb DJ, Khan MS, Nakhla AM, Romas NA 1999 Sex hormone-binding globulin mediates steroid hormone signal transduction at the plasma membrane. J Steroid Biochem Mol Biol 69:481–485[CrossRef][Medline]
32. Ly LP, Handelsman DJ 2005 Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays. Eur J Endocrinol 152:471–478[Abstract/Free Full Text]
33. Bell AG, Corey PN 1974 A sex chromatin and Y body survey of Toronto newborns. Can J Genet Cytol 16:239–250[Medline]
34. Bergemann E 1961 Geschlectschromatinbestimmungen am Neugeborenen. Schweiz Medizinische Wochenschricht 91:292–294
35. Bochkov NP, Bulanov AG, Bloshansky YM, Lazareva TI, Myasnikova LS, Talchuk AA, Tzertzvadze GG 1967 Population geographical study of chromosome disease in man. Genetika 5:57–62
36. Bochkov NP, Kuleshov NP, Chebotarev AN, Alekhin VI, Midian SA 1974 Population cytogenetic investigation of newborns in Moscow. Humangenetik 22:139–152[Medline]
37. Cohen MM, Dahan S, Shaham M 1975 Cytogenetic evaluation of 500 Jerusalem newborn infants. Isr J Med Sci 11:969–977[Medline]
38. Court-Brown WM 1969 Sex chromosome aneuploidy in man and its frequency, with special reference to mental subnormality and criminal behaviour. Int Rev Exp Pathol 7:31–97[Medline]
39. Davidenkova EF, Ponomarenko AM, Verlinskaia DK 1966 [The significance of the method of sex chromatin investigation for the early diagnosis of chromosomal diseases]. Tsitologiia 8:290–292[Medline]
40. Garson OM, Robson MK, Weste SM, Baikie AG 1980 Clinical findings in patients with numerical abnormalities of the X chromosome: a three-year survey of consecutive admissions to a general hospital. Med J Aust 2:33–35[Medline]
41. Gebala A, Zytkiewicz A 1964 [Conflict between the phenotype and chromatin sex of newborn infants according to our studies.] Pediatr Pol 39:557–564[Medline]
42. Goad WB, Robinson A, Puck TT 1976 Incidence of aneuploidy in a human population. Am J Hum Genet 28:62–68[Medline]
43. Hamerton JL, Canning N, Ray M, Smith S 1975 A cytogenetic survey of 14,069 newborn infants. I. Incidence of chromosome abnormalities. Clin Genet 8:223–243[Medline]
44. Harris JS, Heller RH 1974 The detection of Klinefelter’s syndrome at birth. Clin Pediatr (Phila) 13:581–586[Abstract/Free Full Text]
45. Higurashi M, Iijima K, Ishikawa N, Hoshina H, Watanabe N 1979 Incidence of major chromosome aberrations in 12,319 newborn infants in Tokyo. Hum Genet 46:163–172[CrossRef][Medline]
46. Jacobs PA, Melville M, Ratcliffe S, Keay AJ, Syme J 1974 A cytogenetic survey of 11,680 newborn infants. Ann Hum Genet 37:359–376[Medline]
47. Lin CC, Gedeon MM, Griffith P, Smink WK, Newton DR, Wilkie L, Sewell LM 1976 Chromosome analysis on 930 consecutive newborn children using quinacrine fluorescent banding technique. Hum Genet 31:315–328[CrossRef][Medline]
48. Lubs HA, Ruddle FH 1970 Chromosomal abnormalities in the human population: estimation of rates based on New Haven newborn study. Science 169:495–497[Abstract/Free Full Text]
49. Marden PM, Smith DW, McDonald MJ 1964 Congenital anomalies in the newborn infant, including minor variations. A study of 4,412 babies by surface examination for anomalies and buccal smear for sex chromatin. J Pediatr 64:357–371[CrossRef][Medline]
50. Marquez-Monter H, Carnevale-Lopez A, Kofman-Alfaro S 1968 Sex chromatin survey in 3,000 newborn infants in Mexico. Pediatrics 41:664–666[Abstract/Free Full Text]
51. Mikamo K 1968 Sex chromosome abnormalities in newborn infants. Obstet Gynecol 32:688–699[Medline]
52. Milcu SM, Jost A, Maximilian C 1972 [Sex chromatin in 3248 newborn infants from Bukarest]. Anthropol Anz 33:213–218[Medline]
53. Moore KL 1959 Sex reversal in newborn babies. Lancet 1:217–219[CrossRef][Medline]
54. Naik SN, Shah PN 1962 Sex chromatin anomalies in newborn babies in India. Science 136:1116
55. Nielsen J, Wohlert M 1991 Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet 87:81–83[CrossRef][Medline]
56. Orrillo M, Descailleaux J, Pereda J, Hermoza P, Alvarado E 1976 Numerical X-chromosome anomalies at the maternity hospital of Lima. J Genet Hum 24:221–226[Medline]
57. Pantelakis SN, Chryssostomidou OM, Alexiou D, Valaes T, Doxiadis SA 1970 Sex chromatin and chromosome abnormalities among 10,412 liveborn babies. Arch Dis Child 45:87–92[Abstract/Free Full Text]
58. Sergovich F, Valentine GH, Chen AT, Kinch RA, Smout MS 1969 Chromosome aberrations in 2159 consecutive newborn babies. N Engl J Med 280:851–855[Medline]
59. Sorensen K 1987 Klinefelter’s syndrome in childhood, adolescence and youth: a genetic, clinical, developmental, psychiatric and psychological study. Chippenham, UK: Parthenon Publishing
60. Taylor AI, Moores EC 1967 A sex chromatin survey of newborn children in two London hospitals. J Med Genet 4:258–259[Free Full Text]
61. Turner JH, Wald N 1970 Chromosome patterns in a general neonatal population. In: Jacobs PA, Price WH, Law P, eds. Human population cytogenetics. Edinburgh: Edinburgh University Press
62. Van den Berghe H 1970 Nuclear sexing in a population of Congolese metropolitan newborns. Science 169:1318–1320[Abstract/Free Full Text]
63. Verma IC, Bawa B, Ghai OP, Hingorani V, Guha DK 1974 Epidemiology of X-chromatin aberrations in newborns in Delhi. Indian J Med Res 62:676–683[Medline]
64. Wagenbichler P, Golob E 1975 [Detection of sex-chromosome anomalies in newborn infants (author’s translation)]. Wien Klin Wochenschr 87:126–130[Medline]
65. Walzer S, Gerald PS 1977 A chromosome survey of 13,751 male newborns. In: Hook EB, Porter IH, eds. Population cytogenetics. Studies in humans. New York: Academic Press; 45–61
66. Wiesli B 1962 [Comparison of the phenotype and nuclear morphological sex in 3029 newborn infants.] Acta Anat (Basel) 51:377–383[Medline]
67. Marks LS, Mazer NA, Mostaghel E, Hess DL, Dorey FJ, Epstein JI, Veltri RW, Makarov DV, Partin AW, Bostwick DG, Macairan ML, Nelson PS 2006 Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial. JAMA 296:2351–2361[Abstract/Free Full Text]

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