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Correspondence to M.K.
mkathrins@bwh.harvard.edu
doi:10.1038/nrurol.2016.62
Published online 19 Apr 2016
Since the first case reports in 1910 of testicular atrophy after canine hypophysectomy, the hormonal basis
of human reproduction has been an area of evolving
investigation1. An array of treatment modalities are
available for hormonal dysfunction in the setting of
male infertility, but the diagnosis of such dysfunction
and its treatment is often empirical, or guided by the
clinicians judgement, and can be open to interpretation.
Our ability to understand the intratesticular hormonal
environment and its effect on spermatogenesis is limited
by current methods of routine clinical investigation.
In contrast to our understanding of hormonal effects
on male infertility, the science of female reproductive
endocrinology has moved toward an algorithmic,
evidence-based approach. Perhaps the best example
of such a rational, evidence-based treatment approach
to female reproductive-associated hormonal dysfunction is provided by controlled ovarian stimulation
before oocyte retrieval to enable invitro fertilization.
Ovulation stimulation follows an algorithmic approach
to achieve both timely ovulation and pregnancy, avoiding ovarian hyperstimulation syndrome, multiple follicular development, and excessive medication costs.
A 2011 Cochrane review, including 45 randomized
controlled trials (RCTs), compared the effectiveness of
REVIEWS
Key points
Oestradiol is the principal mediator of negative feedback on the hypothalamic
pituitary axis, which illustrates the influence of selective oestrogen receptor
modulators and aromatase inhibitors on male hormonal parameters
Serum hormonal assays are unreliable indicators of intratesticular androgen levels,
and the best approach for determining male androgen status remains elusive
Follicle-stimulating hormone and inhibin B are markers of spermatogenesis and their
relative values in the setting of an intact hypothalamicpituitarygonadal axis provide
important information about testicular function
Targeted hormonal therapy corrects specific hormonal dysfunctions, empirical
hormonal therapy is employed when no underlying cause is identified and the
evidence for empirical therapy is dependent on the type of medication used
A return of sperm to the ejaculate or successful surgical sperm retrieval among men
with azoospermia owing to spermatogenic dysfunction are the most objective
indicators of outcomes of hormonal therapy
Pathophysiology of hypoandrogenism
Hypothalamicpituitarygonadal axis
Secretion of the anterior pituitary gonadotropin hormones
luteinizing hormone (LH) and FSH are stimulated by the
pulsatile release of GnRH and inhibited by the release of
gonadotropin-inhibiting hormone from the hypothalamus9 (FIG.1). LH and FSH share a common subunit and a
distinct subunit10. LH stimulates and promotes testicular
androgen production by the Leydig cells and FSH stimu
lates spermatogenesis supported by Sertoli cells. FSH
and testosterone are both necessary for spermatogenesis
to occur. Indeed, FSH gene mutations in men invari
ably lead to azoospermia and diminished testicular size11.
However, the small number of case reports regarding FSH
receptor mutations in men suggest heterogeneous effects
on male fertility. Case reports have revealed findings ran
ging from severe oligozoospermia to normozoospermia,
including instances of natural conception12. These reports
correlate well with experimental data from FSH-receptor
knockout mouse models13. LHB-knockout mouse models
exhibit diminished serum and intratesticular testosterone
and late-maturation-arrest pathology10,14. Animal models
in this setting are useful for elucidating the underlying
function of gonadotropins in male reproductive physio
logy, but treatment decisions should not be based on such
data alone. In 2001, the peptide kisspeptin was discovered and results from subsequent functional studies have
been published, revealing an agonistic effect on GnRH
release and pulsatile LH release. Kisspeptin has been used
experimentally in men to induce gonadotropin secretion. Increases in LH secretion are more dramatic than
increases in FSH in response to experimental kisspeptin
supplementation; however kisspeptin is not currently
used in clinical practice15.
Other serum indicators of male fertility exist, beyond
FSH and LH. Inhibin B, a glycoprotein heterodimer also
composed of and subunits, is secreted by the testicular
germinal epithelium (primarily Sertoli cells) in response
to FSH (FIG.1). Inhibin B subsequently acts on the anterior
pituitary in a negative-feedback loop, thus inhibiting FSH
production16. Inhibin B is an important indicator of the
degree of spermatogenesis. For example, in instances of
hypospermatogenesis pathology, inhibinB secretion is
decreased and FSH secretion is increased17. In one prospective study, inhibin B and FSH were both found to be
significantly correlated with bulk seminal parameters;
however, the correlation coefficient values were modestly
higher for inhibin B than for FSH (inhibinB:0.48;
P<0.0001, FSH:0.41; P=0.0007). Thus, inhibin B could
be a more sensitive indicator of semen parameters than
FSH18. Conversely, another prospective study of fertile and
infertile men found inhibin B and FSH to be equally predictive of bulk seminal parameters19. Nevertheless, inhibin
B has yet to be widely adopted as part of the routine evalu
ation of male infertility, perhaps owing to increased assay
costs20. Finally, activin is a heterodimer or homodimer
of subunits and is also produced in the testes. Activin
has an agonistic effect on the pituitary secretion of FSH
and its release is inhibited by inhibin B16. However, activin
does not presently have a role in the clinical evaluation of
infertile men.
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Hypothalamus
GnRH
GnIH
Anterior pituitary
FSH
Inhibin B
Activin
Testes
Sertoli cells
In a remarkable demonstration of evolutionary conservation, it is the female hormone oestradiol that exerts
the principle inhibitory feedback on gonadotropin secreSelective oestrogen
tion in men. Oestradiol is generated from testosterone
receptor modulators
by aromatase, a member of the cytochrome p450 super
family (FIG.1). The integral feedback role of oestradiol was
demonstrated in a study involving four men with idiopathic hypogonadotropic hypoandrogenism who were
treated with pulsatile GnRH to normalize pituitary gonadotropin secretion. The men were subsequently treated
Oestradiol
with infusions of testosterone, oestradiol and dihydro
testosterone, a nonaromatizable androgen. Only the testosterone and oestradiol infusions resulted in diminished
serum LH and FSH levels. Dihydrotestostone, which has
Aromatase
inhibitors no potential to be converted to oestradiol had no inhibi
tory effect on gonadotropin secretion24. In other studies,
investigators have localized the negative-feedback effects
Aromatase
of oestradiol to the hypothalamus, where it acts to reduce
LH pulse frequency, and the anterior pituitary, where it
reduces sensitivity to GnRH25,26.
Oestradiol-receptor-knockout mouse models are
Testosterone
(serum ~500 ng/dl)
infertile and have and abnormal spermatogenesis.
Further investigations of such models have revealed
LH
that infertility stems from aberrant proximal epididymal lumen fluid reabsorption and subsequent increases
in intraluminal pressure27,28. Conversely, at the testicular
level, basal oestradiol is necessary for normal spermato
genesis, as proven by case studies of infertile men with
Leydig cells
congenital aromatase deficiency. In fact, the ARO1
(also known as CYP19A1) and oestradiol receptors
are also expressed in Sertoli, Leydig, and germ cells of
Testosterone
(~60,000 ng/dl)
fertile men26,29,30.
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Box 1 | Types of hypogonadotropic hypoandrogenism
Congenital hypogonadotropic hypoandrogenism
Kallman syndrome (when associated with anosmia)
Adult-onset hypogonadotropic hypoandrogenism
Underlying medical condition:
-- Hyperprolactinaemia
-- Pituitary adenoma
-- Hypopituitarism
-- Hypothyroidism
-- Sickle cell disease
-- Haemochromatosis
-- Opiate-induced
-- Exogenous testosterone or anabolic steroid use
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loosely albumin-bound testosterone)52. Several conditions exist that might predispose men to derangements
in serum SHBG concentrations and affect the serum
concentration of free testosterone and bioavailable
testosterone, including liver dysfunction, thyroid dysfunction, and obesity. Advanced age is one of the most
important of these conditions, and is associated with
increases in serum SHBG concentrations independent
of body-mass index53,54.
The Endocrine Society clinical practice guidelines
also recommend measurement of free testosterone or
bioavailable testosterone in the event of equivocal findings from total testosterone assays50. Indeed, serum total
testosterone concentrations ranging from 280350ng/dl
lack sufficient sensitivity to rule out diminished free testosterone. However, a total testosterone threshold of
400ng/dl has a sensitivity of 98.2% for ruling out low free
testosterone levels55. In a retrospective analysis of 73 men
presenting for fertility evaluation that used bioavailable
testosterone as the most accurate indicator of androgen
status, investigators found that low total testosterone
yielded a positive-predictive value (PPV) of 50% for
abnormal bioavailable testosterone. Specifically, among
men >40years of age, the PPV of total testosterone was
59% and among men <40years of age the PPV of total
testosterone was only 20%, which is unsurprising given
the naturally increased SHBG serum concentrations in
older men. Thus, overall, total testosterone is a poor predictor of androgen status when bioavailable testosterone
is employed as the gold standard56. In our clinical practice,
we routinely rely on bioavailable testosterone as the gauge
of androgen status for men p
resenting withinfertility.
The specific determination of serum androgen levels
is also fraught with uncertainty. A survey conducted
by the College of American Pathologists used a single
sample from a hypoandrogenic man that was processed
independently by 1,100 pathology laboratories across
the USA. The results of these analyses showed a 32.2%
coefficient of variability for total testosterone, indicating highly inconsistent laboratory results. Specifically,
free testosterone can be directly measured by ultrafiltration, equilibrium dialysis, or immunoassay, the latter
of which is particularly unreliable, whereas equilibrium dialysis is the most reliable method. Bioavailable
testosterone levels can be measured using ammonium
sulfate precipitate, which is unreliable52,57. Moreover,
these methods are time-intensive, costly, not suited to
automation, and subject to difficult to control laboratory variables including temperature, which can affect
the final results52. To address these limitations, several
algorithms for calculating bioavailable testosterone or
free testosterone levels have been developed from assays
of total testosterone, SHBG, and albumin. These algorithms, if adopted, must be validated on a casebycase
basis by individual clinical laboratories58. Perhaps the
most widely adopted algorithm for calculating free testosterone and bioavailable testosterone was published by
Vermeulen and colleagues59, who proposed lower-limit
reference values for young, healthy men of 0.23nmol/l
(6ng/dl) for free testosterone and 5.3nmol/l (153ng/dl)
for bioavailabletestosterone60.
REVIEWS
bioavailable testosterone or free testosterone values
were not compared using the bioactive androgen assay,
so the clinical significance of data from this novel assay
remains uncertain.
Roth etal.70 performed a similar experiment by analysing testicular aspirations from fertile men. Contrary
to the findings of Jarow and colleagues68, the authors
found that serum testosterone and intratesticular testosterone, drawn at the same time, did correlate strongly
(r=0.67, P=0.03). Interestingly, they also found signifi
cant intrasubject variability in intratesticular testosterone levels which correlated very strongly with serum
LH (r=0.87, P=001). They hypothesized that the wellknown pulsatility of LH secretion could reflect similarly
pulsatile secretion of intratesticular testosterone. Further
evidence for the pulsatile secretion of intratesticular testosterone was provided by a study of testicular testosterone and oestradiol concentrations in cannulated gonadal
veins of men with varicoceles. Sampling every 15minutes revealed hourly testosterone pulses (35 pulses
per hour) with a mean amplitude of 17642ng/ml, a
6.6fold increase from the nadir71. However, currently,
the effect of intratesticular testosterone pulsatility on
spermatogenesis is unknown.
Several studies of infertile men and intratesticular androgen status have been performed. In one such
study, investigators found that intratesticular testosterone significantly correlated with increased serum
LH (r=0.67; P<0.001) and reduced testicular volume (P<0.001)72. Interestingly, Marie and colleagues73
found that infertile men with normal-range FSH had
elevated levels of intratesticular testosterone (P<0.01)
and intratesticular oestradiol (P<0.05), and a decreased
intratesticular testosterone:oestradiol ratio (P<0.05)
when compared with fertile controls. Conversely,
Shinjo etal.74 noted similar intratesticular testosterone
concentrations between men with ASD who underwent
a successful first microsurgical testicular sperm extraction (mTESE) and men who underwent an unsuccessful
surgery. However, men who were treated with salvage
exogenous human chorionic gonadotropin (hCG) and
underwent a successful second mTESE were more likely
to have lower baseline intratesticular testosterone levels
than men who failed salvage therapy, indicating a role for
targeted hormone therapy in this population.
The relationship between intratesticular testosterone and the clinical presentation of infertility remains
unclear, but researchers have also sought correlations
between testicular pathology for examining the degree
of spermatogenic dysfunction and intratesticular testosterone concentrations. Lardone etal.75 performed
a prospective study of 261 men with oligozoospermia
or azoospermia, including 68 men with obstructive
azoospermia who served as controls. The investigators
found that testicular pathological specimens with worsening degrees of spermatogenic dysfunction actually
contained increasing concentrations of intratesticular
testosterone relative to controls. Strong correlations
were also observed between worsening testicular spermatogenic pathology, larger Leydig cell clusters, and
decreased serum testosterone:LH ratio. These results
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demonstrated that testosterone supplementation might
only induce spermatogenesis in the presence of a transgenic AR85,86. Finally, analyses of rat models of androgen
suppression (testosterone implants, oestradiol implants,
and FSH antibody) have revealed that the level of spermatogenic dysfunction is at the final stage of spermiation, owing to derangements in cell-cell adhesions
between spermatids and the Sertoli cell84,87.
Attempts to clinically correlate AR distribution
and function with the degree of infertility have been
unsuccessful thus far. Kato etal.81 discovered higher AR
density in men with ASD than in men with obstructive
azoospermia. Surprisingly, no correlation was found
between AR density and testicular volume, serum testosterone levels, serum gonadotropin levels, or intratesticular testosterone concentration. Furthermore,
exogenous FSH triggered an increase in AR density
while hCG therapy had no effect, underscoring the
importance of FSH-dependent Sertoli cell AR expression. Thus, gonadotropin monotherapy with hCG
would be inadequate in the setting of hypogonadotropic
hypoandrogenism. Attempts to associate the degree of
spermatogenic dysfunction and bulk seminal param
eters with polyglutamine polymorphisms in the AR have
yielded conflicting results, with some studies identifying
correlations and others not8891. Thus, FSH-dependent
AR expression is a necessary component for complete
spermatogenesis; however, accurate functional assays of
AR activation and, therefore, true androgen status, are
sorely lacking in clinical practice.
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Table 1 | Prospective trials of empirical therapy with selective oestrogen receptor modulators
Author and Trial design
publication
year
Treatment
Baseline male
factor
Pregnancy rate
Foss etal.103
1972
RCT, double-blind,
CC 100mg daily for
placebo-controlled, three 10day periods
cross-over
successively versus
placebo
n=114
Idiopathic
infertility
NR
Ronnberg
etal.151
1980
RCT, double-blind,
CC 50mg daily
placebo-controlled, versus placebo for
cross-over
34months (3months
washout)
n=30
Euandrogenic
infertile men
CC: n=3
Placebo: n=1
Abel etal.152
1982
RCT, non-blind,
non-placebocontrolled
n=179
Infertile men
NR
CC: 17%
VitaminC 13%
RCT, placebo
controlled,
non-double-blinded
(or undescribed
blinding)
CC 25mg (n=11) or
50mg daily (n=18)
versus placebo (n=7)
versus mesterolone
(n=12) versus
pentoxifylline (n=11)
versus testosterone
enanthate (n=15) for
6months
n=46
Euandrogenic
idiopathic
oligozoospermia
n=23
Euandrogenic
idiopathic
oligozoospermia
Wang
etal.153
1983
Sokol
etal.154
1988
RCT, double-blind,
placebo-controlled
million/ml*
Placebo: sperm concentration
unchanged
CC: 9.09%
Placebo: 44.44%
Check
etal.155
1989
RCT, non-blind,
non-placebo-controlled
n=100
Idiopathic
infertility
(normal semen
parameters)
CC: 58%
VitaminC: 16%*
WHO156
1992
RCT, double-blind
n=191
Idiopathic
abnormal semen
parameters
No significant changes
CC: 8.1%
Placebo: 11.7%
Patankar
etal.157
2007
Open-label
n=25
Group 1: Motile sperm
Severe
concentration: 1.740.25
oligozoospermia
3.920.83million/ml*
(Group 1)
Group 2: Motile sperm
n=40, moderate
concentration 8.270.4
oligozoospermia
10.050.56million/ml
(Group 2)
NR
Ghanem
etal.158
2010
RCT, double-blind,
placebo-controlled
n=30
CC and
vitaminE
n=30
Placebo
Idiopathic OAT
CC: 36.7%
Placebo: 13.3%*
Count (million)
CC: 10.24.14 1815*
Placebo: 11.37.13 128.6
Motility (%)
CC: 3319 3421
Placebo: 3018 2416
Abnormal forms (%)
CC: 4116 3818
Placebo: 4115 5114
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Table 1 (cont.) | Prospective trials of empirical therapy with selective oestrogen receptor modulators
Author and Trial design
publication
year
Treatment
Baseline male
factor
Pregnancy rate
Moradi
etal.159
2010
RCT
lcarnitine versus
CC 25mg daily for
3months
n=52
Idiopathic
infertility
Sperm concentration
improvement* (no difference from
lcarnitine)
Motility improvement* (greater
improvement than lcarnitine)
Morphology improvement*
(greater improvement than
lcarnitine)
NR
ElSheikh
etal.160
2015
RCT
VitaminE versus CC
25mg daily versus
vitaminE+CC for
6months
n=90 (1:1:1)
Idiopathic OAT
Sperm concentration:
VitaminE: no change
CC: improvement*
VitaminE+CC: improvement
NR
Sperm motility:
VitaminE: improvement*
CC: improvement*
VitaminE+CC: improvement*
CC, clomiphene citrate; FSH, follicle-stimulating hormone; NR, not reported; OAT, oligoasthenoteratozoospermia; RCT, randomized controlled trial *Statistically
significant.
Aromatase inhibitors
Unlike the SERMs, targeted therapy with aromatase inhibitors has been repeatedly studied.
Aromataseinhibitors include the steroidal agent testolactone, the nonsteroidal third-generation agent
letrozole, and fourth-generation nonsteroidal agent,
anastrozole, which has the highest relative aromatase
enzyme selectivity (BOX 2) . Targeted treatment is
directed toward correction of a diminished testosterone:oestrogen ratio114,115. Cavallini etal.116 performed a
double-blind, placebo-controlled RCT of targeted letrozole therapy for 6months in men with azozoospermia
or cryptozoospermia with a testosterone:oestrogen ratio
<10. Their results demonstrated significant improvements in bulk seminal parameters compared with placebo including resolution of all instances of ASD (sperm
concentration P<0.01, sperm percentage motility
REVIEWS
P<0.01). No spontaneous pregnancies were reported in
either group. Two notable single-institution retrospective series of men with oligozoospermia and testosterone:oestrogen ratio <10 have been published66,117. Of the
men with pretreatment and post-treatment semen analyses, anastrozole and testolactone yielded similar overall
improvements in bulk seminal parameters. Anastrozole
improved the testosterone:oestrogen ratio to a greater
extent, but men with Klinefelter syndrome responded
more readily to testolactone. Similarly, Gregoriou
etal.115 prospectively studied the relative effects of
6months of therapy with either anastrozole (1.0mg
daily) or letrozole (2.5mg daily) in 29 infertile men
with testosterone:oestrogen ratio <10. Semen parameters improved in >70% of patients in both treatment
arms. Saylam etal.67 examined 27 infertile men with
a testosterone:oestrogen ratio <10 who were treated
prospectively with 2.5mg letrozole for 6months. These
authors also observed significant overall improvements
in the testosterone:oestrogen ratio (P=0.001) and all
bulk seminal parameters evaluated (P<0.05). Thus, the
evidence for targeted therapy with aromatase inhibitors
is particularly promising.
Gonadotropin therapy
Therapeutic gonadotropin preparations have been
used clinically for the past 100years. These treatments
evolved from animal-based preparations to human
urine extracts then to highly purified recombinant
formulations. Purified injectable human menopausal
gonadotropin (hMG) contains bioactive FSH and LH
in 75IU formulations, with up to 70% gonadotropin
purity (BOX2). Two recombinant formulations of FSH
are commercially available, GonalF (Merck KGaA,
Germany) and Puregon (N.V. Organon, Netherlands),
which are notable for their higher purity than hMG.
Finally, hCG is available in a recombinant or urine-
derived formulation118,119. The relatively lower purity
of hMG than recombinant forms of FSH could be concerning for female patients with infertility in whom
the ratio of LH to FSH is vitally important for achieving
controlled ovarian stimulation such differences are
of negligible importance for infertile men given that the
ratio of LH to FSH does not play a clinically relevant
role in spermatogenesis. The lower cost of urine-derived
formulations compared with recombinant formulations
might, ultimately, prove to be the more important driver
of treatment choice.
Similar to SERM treatment, empirical gonadotropin
therapy has been used to treat idiopathic male infertility. Caroppo etal.120 performed a prospective open-label
trial of 33 men with idiopathic oligoasthenoteratozoospermia treated with 150IU of recombinant FSH for
3months. The authors observed significant improvements in all bulk seminal parameters after treatment,
but not in the untreated control group (P<0.05 for
sperm count and motile sperm. P<0.01 for percent
normal morphology, and P<0.001 for percent viable sperm). Of note, the baseline serum FSH level for
patients in the experimental arm was 9.686.05IU/l,
which reflects a population of men with normal range
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Initial hormonal evaluation of infertile male
(total testosterone, FSH, LH, oestradiol, albumin and SHBG)
Yes
Is bioavailable testosterone
<155 ng/dl?
Yes
No
No
Yes
No
Aromatase inhibitor
therapy
Yes
Yes
Yes
Check semen analysis,
total testosterone, PSA
and CBC in 4 months
No
No
Add hCG therapy
Figure 2 | A simple algorithm for diagnosing and treating hormonal dysfunction in the setting of infertility to
assist clinicians in the decision-making process. CBC, complete blood count; FSH, follicle-stimulating
hormone;
hCG,
Nature Reviews
| Urology
human chorionic gonadotropin; hMG, human menopausal gonadotropin; LH, luteinizing hormone; r, recombinant; SHBG,
sex hormone-binding globulin.
experiments involving men treated with exogenous testosterone (which induces hypogonadotropic hypoandrogenism and azoospermia) have shown that treatment
with either FSH or hCG might be sufficient to induce
normal spermatogenesis141,142.
The optimum recovery regimen and whether or
not treatment offers any advantage over watchful waiting for recovery of spermatogenesis remain unknown;
however a simple algorithm for diagnosing and treating
hormonal dysfunction in the setting of infertility would
assist clinicians in the decision-making process (FIG.2).
REVIEWS
1,054 men, targeted hormonal therapy for hypoandrogenic men with ASD did not yield any differences in
SSR rates, pregnancy rates, or live birth rates compared
with rates in untreated men143. However, a sub-analysis
of this same cohort revealed that SSR rates in men with
non-mosaic Klinefelter syndrome treated with hormonal therapy (mostly aromatase inhibitors with or
without exogenous testosterone supplementation) were
significantly higher for men who experienced adequate
improvements in serum androgen levels than in men
who did not respond (77% versus 55%; P=0.05)144,145.
Shiraishi etal.146 studied men who had an ineffective
initial mTESE and were subsequently treated with hormonal therapy. The treated men experienced a 21% SSR
rate compared with a 0% rate among untreated men.
Their treatment regimen consisted of high dosage hCG
(5,000IU three times per week for 3months), with
recombinant FSH added to the treatment regimen only if
serum FSH levels decreased from baseline. Interestingly,
53% of men experienced such a decrease in FSH from
baseline secondary to supraphysiologic serum testosterone, which serves as an important warning to monitor
such FSH levels if high-dose hCG monotherapy is pursued. Furthermore, men with severe hypoandrogenism
(total testosterone <200ng/dl) were excluded from their
study, which limits the applicability of their results146.
None of these retrospective studies included power
analyses to evaluate their results, which undermines the
relevance of the study findings.
Several prospective uncontrolled trials have been
performed to explore this important clinical presentation. Hussein etal.147 conducted a trial of clomiphene
citrate therapy in 42 men with ASD, of which 43% had
hypoandrogenism based on serum total testosterone
levels. After treatment for a mean duration of 5months,
64% of men developed sperm in their ejaculate and all
remaining men underwent successful mTESE. Post-hoc
analyses of preoperative testicular pathology indicated
that early maturation arrest was a negative prognostic
indicator of the development of ejaculated sperm, after
excluding men with Sertoli-cell-only syndrome (SCOS)
pathology from enrolment in the study. This group
performed a second controlled open-label prospective
trial of clomiphene citrate therapy before mTESE in
496 men. Men who failed to achieve post-treatment
FSH levels 50% greater than baseline were treated with
additional injectable gonadotropin therapy. Importantly,
the authors noted significantly higher SSR rates in the
experimental arms than in the untreated control arm
(61.7% versus 33.6%, P<0.001)101. Aydos etal.148 similarly
1.
2.
3.
Conclusions
Treatment of male infertility has evolved to encompass
physicians who routinely address complex hormonal
therapy in addition to surgery. Our knowledge of the
genetic aspects of male fertility has moved forward,
but research into hormonal therapy for men has largely
relied on heterogeneous treatment regimens with unreliable outcomes. The information garnered from such
studies is important, although it pales in comparison
to the level of evidence available to our colleagues in
female reproductive endocrinology. Investigations
into female infertility benefit from reliance on objective, verifiable outcomes such as ovulation, biochemical pregnancy, and clinical pregnancy. Meanwhile, the
male counterpart has been hampered by the necessary
dependence on bulk seminal parameters, which are
notoriously poor predictors of fertility potential. Perhaps
the only truly reliable semen analysis is one indicating
azoospermia and that is where the most exciting clinical outcomes research has focused. The performance
of multi-institutional, high-quality trials with sufficient
enrolment numbers and meaningful and reliable outcomes, and the development of reference databases are
vital to best treat ourpatients.
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Competing interests
Author contributions
M.K. wrote the article, both authors researched data for the
article, discussed the content and reviewed and edited
themanuscript before submission.
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