REVIEW

CURRENT
OPINION Testicular growth and development in puberty
Jaakko J. Koskenniemi, Helena E. Virtanen, and Jorma Toppari

Purpose of review
To describe pubertal testicular growth in humans, changes in testicular cell populations that result in
testicular growth, and the role of testosterone and gonadotrophins follicle-stimulating hormone (FSH) and
luteinizing hormone (LH) in testicular growth. When human data were not available, studies in nonhuman
primates and/or rodents were used as surrogates.
Recent findings
Testicular growth in puberty follows a sigmoidal growth curve, with a large variation in timing of testicular
growth and adult testicular volume. Testicular growth early in puberty is due to increase in Sertoli cell
number and length of seminiferous tubules, whereas the largest and fastest growth results from the increase
in the diameter of the seminiferous tubules first due to spermatogonial proliferation and then due to the
expansion of meiotic and haploid germ cells. FSH stimulates Sertoli cell and spermatogonial proliferation,
whereas LH/testosterone is mandatory to complete spermatogenesis. However, FSH and LH/testosterone
work in synergy and are both needed for normal spermatogenesis.
Summary
Testicular growth during puberty is rapid, and mostly due to germ cell expansion and growth in
seminiferous tubule diameter triggered by androgens. Pre-treatment with FSH before the induction of
puberty may improve the treatment of hypogonadotropic hypogonadism, but remains to be proven.
Keywords
FSH, gonadotropins, LH, testis, testosterone

INTRODUCTION Our longitudinal follow-up of 51 Finnish boys

Adult testes consist mostly of germ cells [1,2], and
testicular volume correlates with sperm output and
&&
concentration [3 ]. Here, we review studies on
testicular growth from childhood to adult in human
and nonhuman primates, discuss the quantitative
with a history of congenital cryptorchidism and 65
controls examined once every 6 months during
puberty by ultrasound confirmed that testicular
growth within individual patients followed a sig-
moidal curve very similar to the median curve in the
&&

changes in testicular tissue during growth, and hor-
monal factors that control the testicular growth
based on studies with receptor knockout mice, exper-
imental studies with primates, and human case
reports. Finally, the relevance of these data for clinical
practice is discussed in context of studies on induc-
tion of testicular growth and spermatogenesis in
patients with hypogonadotropic hypogonadism.
THE PATTERN OF TESTICULAR GROWTH
IN HUMANS
Testicular size doubles from early childhood to pre-
puberty [2,4], after which the testicular growth
peaks during puberty and adult testicular volume
&&
is reached [4,5,6,7 ]. A recent, cross-sectional Dutch
study showed that testicular growth follows sigmoi-
dal curve with an approximate average pre-pubertal
volume of 0.6 ml and post-pubertal volume of 13 ml,
&&
based on ultrasound measurements [4,7 ].
cross-sectional Dutch study, shown in Fig. 1 [7 ]. In
the study, testicular volume during puberty was
modelled assuming that testicular growth in each
patient could be represented with four parameters
describing pre-pubertal and post-pubertal testicular
volume, timing of pubertal growth, and the
duration of testicular growth. This allowed us to
summarize the typical longitudinal testicular
growth curve, and the variability in the shape of
the testicular growth pattern. As shown in Fig. 1,
substantial inter-individual variation was noticed in
Institute of Biomedicine, Department of Physiology, University of Turku,
and Department of Paediatrics, Turku University Hospital, Turku, Finland
Correspondence to Jorma Toppari, MD, PhD, Institute of Biomedicine,
Department of Physiology, University of Turku, and Department of Paedi-
atrics, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku,
Finland. Tel: +358 401802600; e-mail: jorma.toppari@utu.fi
Curr Opin Endocrinol Diabetes Obes 2017, 24:215–224
DOI:10.1097/MED.0000000000000339

1752-296X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved. www.co-endocrinology.com

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Androgens
KEY POINTS
 Testicular growth during puberty is rapid with large
variation in timing and post-pubertal volume.
 On tissue level, pubertal testicular growth is due to
increase in length and diameter of seminiferous tubules
due to successive increase in Sertoli cells,
spermatogonia, spermatocytes, and spermatids.
 FSH promotes increase in Sertoli cells and
spermatogonia early during puberty, whereas LH/
testosterone is needed to complete spermatogenesis.
 Pre-treatment with FSH succeeded by the combination
of FSH and hCG may increase the Sertoli cell numbers
in patients with hypogonadotropic hypogonadism, but
remains to be proven.
the timing of pubertal testicular growth and the
post-pubertal testicular volume among healthy
boys, whereas the pre-pubertal testicular volume
was very similar across patients. Approximately half
of the testicular growth took place between 12.7 and
14.1 years, demonstrating that testicular growth
during puberty is rapid.
Pubertal testicular growth is often evaluated by
Prader orchidometer, a set of 12 rotational ellipsoids
from 1 to 25 ml, due to both historical and practical
reasons. Unlike ultrasound, orchidometer system-
atically overestimated the testicular volume com-
pared to water displacement [8]. It is often stated
that volumes measured by orchidometer and
ultrasound correlate well. However, even highly
significant correlation between two methods does
not guarantee clinically acceptable agreement [9].
When the agreement between orchidometer
and ultrasound was analysed with a statistically
more appropriate Bland–Altman analysis [9], the
between-measurement difference and variability
were large even at small volumes (95% limit of
agreement was 2.5–10 ml at testicular volume of
5 ml by ultrasound based on ellipsoid formula)
and both increased further with testicular size
&&
[7 ]. Although other studies have not reported
95% limits of agreement, based on published
figures, a similar increasing between-measurement
variability is apparent in many [8,10–14], but not
all studies [15,16]. Thus, ultrasound cannot be
replaced by orchidometer without a significant
loss of precision.
Despite this, there is strong evidence to justify
the use of Prader orchidometer in estimation of
pubertal onset. According to Prader’s classical obser-
vations, testes grew mostly before and after the
attainment of 5 ml volume by orchidometer [5],
216 www.co-endocrinology.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
15
(a)
10
Mean
Modeled
5
Testicular volume by US (mL)
0
15
(b) 15
(c)
10 10
5 5
0 0
15
(d) 15
(e)
10 10
5 5
0 0
9 12 15 18 9 12 15 18
Age (years)
FIGURE 1. Testicular growth pattern by ultrasound in
pubertal boys. (a) Modelled longitudinal testicular growth
patterns in 65 healthy Finnish boys are shown as grey
curves in the study by Sadov et al. [7]. Black solid line
shows the mean testicular volume. Black dashed line
indicates typical testicular growth pattern in the non-linear
mixed-effect model. (b–e) Inter-individual variation in the four
parameters representing the shape of the testicular growth
curve including pre-pubertal (b) and post-pubertal testicular
volume (c), timing of testicular growth (d), and duration of
testicular growth (e) in the same study. Solid black line
shows the typical testicular growth curve based on non-linear
mixed-effect model, dashed lines show the 1 SD, and grey-
shaded areas mark the area within 2 SDs from the mean.
Pre-pubertal testicular volume in (b) shows little variation,
thus showing almost no shading.
and after testes reached the volume at least 3 ml
by orchidometer, further testicular growth was
noted within 6, 12, and 24 months in 72, 90, and
100% of the patients, respectively [6]. Another study
confirmed that further testicular growth or matu-
ration of the pubic hair occurs within 6 months in
82% after the attainment of testicular volume of
above 3 ml by orchidometer [17]. Finally, the vol-
&
ume of 3 ml [18 ] or 4 ml [4] by orchidometer
is roughly 2 SDs larger than mean pre-pubertal
testicular volume, suggesting that the theoretical
Volume 24  Number 3  June 2017
 Testicular growth in puberty Koskenniemi et al.

likelihood that a boy presenting with above 3 ml
testes has not experienced any pubertal testicular
growth is only approximately 2.5% based on math-
ematical properties of the normal distribution.
Thus, the age at the attainment of above 3 ml
(equivalent to 4 ml) in testicular volume is the first
reliable marker of the onset of puberty. However,
pubertal development should not be regarded as
binary, but as continuous, because testicular growth
slowly accelerates and testicular volume multiplies
long before volumes corresponding to more than
&&
3 ml by orchidometer [4,7 ].
The above 3 ml testicular volume is attained by
the age of 10.8 years in Finland and Turkey (means)
&&
[7 ,19], 10.7 in Denmark (mean) and Japan
(median, originally reported 11.0 years for the
attainment of 3 ml) [20,21], and 10.6 in the Neth-
erlands (median) [4]. During the past decades, there
is evidence for, at most, a very subtle decrease
(0.26 years) in the age at attainment of above 3 ml
in Denmark, which is supported by a similar slight
change in the growth pattern in stature in Finnish
boys [22]. The evidence for possible temporal
changes in timing of male puberty has been pre-
viously extensively reviewed by Tinggaard et al. [23].
THE CHANGES IN TESTICULAR TISSUE
POPULATIONS REFLECTED IN
TESTICULAR GROWTH
Testicular tissue consists of seminiferous tubules,
which are formed by Sertoli cells and germ cells,
and are bordered by peritubular myoid cells, and the
interstitium is located between the tubules. Figure 2
shows the relative changes in testicular tissue com-
position and distribution of cell populations from
birth to puberty in Cebus monkeys, extracted from
the study by Rey et al. [24]. The study [24], studies on

1.5
Testicular volume (ml)

1.0

0.5

0.0

80
Share of testicular volume (%)

60
Interstitium
Seminiferous
tubule
40

20
Share of total tubular cell number (%)

GC
75
PreSG

50 SC

SG

25 SpC

St
0
Neonate Infant Early puberty Late puberty

FIGURE 2. Testicular growth and changes in testicular tissue during puberty in Cebus monkeys. (a) Testicular growth in Cebus
monkeys in the study by Rey et al. [24] based on testicular weights after castration (the weights were multiplied by 1 to obtain
testicular volume). Grey-shaded area shows the approximate 95% reference range (2 SD). (b) Relative share of testicular
volume by seminiferous tubules and the interstitium from birth to late puberty. (c) Share of each tubular cell type of the total tubular
cell numbers. GC, gonocyte; pre-SG, pre-spermatogonia; SC, Sertoli cell; SG, spermatogonia; SpC, spermatocyte; St, spermatid.

1752-296X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved. www.co-endocrinology.com 217

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Androgens
Rhesus monkey [25,26], and a human autopsy study
[1,2] suggest that most of the testicular growth
before puberty is due to elongation of the seminif-
erous cords as a result of the proliferation of Sertoli
cells. In both men, and in Cebus and Rhesus mon-
keys, Sertoli cells proliferate during neonatal period
and until early puberty [1,24–27].
In contrast to childhood, pubertal testicular
growth spurt in all three species coincided with an
increase in seminiferous tubule diameter [1,2,24,25].
In Rhesus monkeys, this was first due to proliferation
of Sertoli cells and then of undifferentiated type A
spermatogonia [27]. Later, testicular growth was due
to exponential increase in more differentiated germ
cells due to the progress of spermatogenesis [24].
DIFFERENTIATION OF THE SERTOLI CELLS
DURING PUBERTY
Despite the dominant effect of germ cells on final
testicular volume, Sertoli cells exert an indirect
effect on testicular growth and determine the
maximal number of germ cells and adult testicular
volume [28]. However, this maximal carrying
capacity of the Sertoli cells is, perhaps, not reached
even in adult men [29–32], as discussed later.
Termination of Sertoli cell proliferation during
puberty precedes the completion of spermatogenesis.
During the Sertoli cell differentiation in puberty,
neighbouring Sertoli cells form tight junctions, which
contribute to the blood–testis barrier that permits the
establishment of a special microenvironment needed
for spermatogenesis [33,34]. Furthermore, Sertoli cell
morphology changes to scaffolding that provides
habitats for germ cells. These changes are preceded
by increased expression of androgen receptor (AR)
in Sertoli cells and coincide with increased levels of
circulating testosterone and decreased levels of anti-
Müllerian hormone (AMH) [35–38] – a protein
expressed exclusively in Sertoli cells.
Testosterone and AMH levels were inversely cor-
related among boys during puberty [35,39], and AMH
levels remained high in adulthood among patients
who lacked functional AR due to inactivating gene
mutation [40], suggesting that androgens down-
regulate AMH expression. The down-regulation is
complemented by meiotic entry of germ cells accord-
ing to both experimental and human data [38,41,42].
EFFECTS OF FOLLICLE-STIMULATING
HORMONE, LUTEINIZING HORMONE, AND
ANDROGENS ON TESTICULAR GROWTH IN
MOUSE MODELS
The effects of androgens and pituitary gonado-
tropins luteinizing hormone (LH) and follicle-
218 www.co-endocrinology.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
stimulating hormone (FSH) on Sertoli cell function
and testicular growth have been studied for decades.
Recently, this has been further elucidated by pro-
duction of mice with cell-specific or global inacti-
vation of their cognate receptors. Most aspects of
this work is summarized in the Fig. 3 adopted from
the study by O’Shaughnessy et al. [43].
Follicle-stimulating hormone seems to be the
main hormone promoting early pubertal testicular
growth in mice. Mice lacking FSH receptors (FSHRs)
had reduced Sertoli cell and spermatogonial prolifer-
ation early in puberty, which was reflected by
declined testicular growth [43–45]. However, testic-
ular growth and proliferation of germ cells later
during puberty were comparable to wild-type mice,
although without any apparent catch-up growth
[43]. Furthermore, all stages of spermatogenesis
were present, and adult male FSHR knockout mice
were fertile or at least sub-fertile in all studies.
Whereas FSH seems to optimize fecundity,
androgens secreted from Leydig cells are indispen-
sable for male fertility. Unlike germ cells, Sertoli
cells, peritubular myoid cells, and Leydig cells
express AR [36,37], and they mediate the effects of
androgens on germ cells. Female external pheno-
type was common in genetically male mice with
ubiquitous AR inactivation due to spontaneous tfm
gene mutation, and spermatogenesis did not process
beyond spermatocytes [46,47]. Furthermore, these
mice experienced a reduction in Sertoli cell number
in early puberty and germ cell number in late pub-
erty [43,45,48]. However, these differences may be
in part due to disruption of testicular descent, as
extra-testicular targeting of the AR in the gubernac-
ulum – the anatomical structure that guides the
testicular descent – also results in declined testicular
growth in mice [49].
In contrast to ubiquitous inactivation of AR,
cell-specific targeting of AR in Sertoli cells, peritub-
ular myoid cells, or Leydig cells does not interfere
with testicular descent. Sertoli cell and spermatogo-
nial proliferation early during puberty appeared
relatively unchanged by the Sertoli cell-specific abla-
tion of the AR (SCARKO mice) [43,50]. In contrast,
spermatogenesis did not progress beyond early
meiosis, and consequently testicular growth was
substantially declined late in puberty [48,51,52].
Thus, SCARKO mice did not produce sperm and
were infertile [52]. A peritubular myoid cell-specific
targeting of AR in mice (PTMARKO mice) led to a
marked decrease in spermatocyte and spermatid
numbers [53]. Furthermore, seminiferous tubule
lumen volume and diameter were reduced,
suggesting a Sertoli cell dysfunction. The knockout
mice were also infertile due to almost complete
absence of sperm [53]. However, similar to SCARKO
Volume 24  Number 3  June 2017
 Testicular growth in puberty Koskenniemi et al.

FIGURE 3. Changes in testicular characteristics and cell numbers during puberty in androgen and/or FSH receptor knockout
mice. Reproduced with permission from O’Shaughnessy et al. [43]. ARKO, androgen receptor knockout mice; FSHRKO, FSH
receptor knockout mice; FSHRKO-ARKO, double knockout (FSHRKO and ARKO) mice; FSHRKO-SCARKO, double knockout
(FSHRKO and SCARKO) mice; SCARKO, Sertoli cell-specific androgen receptor knockout mice.

mice, Sertoli cell number and nuclear size were
unaltered. Also, Leydig cell-specific AR ablation
(L-ARy/- mice) reduced testicular growth, halted
spermatogenesis at secondary spermatocyte and
round spermatid level rendering the mice infertile
[54].
In the opposite spectrum of androgen levels, a
recent mice model prematurely over-expressing AR
in Sertoli cells was reported to have 50% smaller
&
testes with 70% smaller number of Sertoli cells [55 ].
In contrast, numbers of late meiotic germ cells
relative to Sertoli cell numbers were abnormally
high leading to increased germ cell apoptosis
&
compared to wild-type [55 ]. This demonstrates that
in principle excessive and too early androgen action
can be harmful for testicular development.
Mice without a functional LH receptor had nor-
mal prenatal testicular development [rodents lack
human chorionic gonadotropin (hCG)], whereas
postnatal testicular growth was compromised, and
Leydig cells disappeared by postnatal day 20 [56].
Furthermore, similar to SCARKO, tfm, and L-ARy/-
mice, sperm production was halted, and did not
proceed beyond round spermatids [57].
Taken together, these studies suggest that, in
mice, pre-pubertal and pubertal FSH optimizes

1752-296X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved. www.co-endocrinology.com 219

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Androgens
fertility by promoting spermatogonial and Sertoli
cell proliferation and survival, whereas androgens
are needed to enter and complete spermatogenesis
and thus finish the testicular growth. This is sup-
ported by studies with a prior mouse model with
undetected gonadotropin levels due to inactivating
GnRH mutation, in which testosterone/dihydrotes-
tosterone substitution alone initiated qualitatively
complete spermatogenesis with reduced absolute
number of Sertoli and germ cells, but normal ratio
between the two [47]. Complementation of testos-
terone with over-expression of transgenic FSH or
FSH injections starting from day of birth greatly
enhanced the number of Sertoli cells, spermatogo-
nia, and spermatocytes, whereas the ratio between
Sertoli and germ cells remained unchanged [58,59].
ROLE OF FOLLICLE-STIMULATING
HORMONE, LUTEINIZING HORMONE, AND
ANDROGENS IN TESTICULAR GROWTH IN
HUMANS AND NONHUMAN PRIMATES
Although the role of FSH and LH/testosterone
appears clear in mice, the data must be extrapolated
to humans with caution. In contrast to humans and
non-human primates, rodents lack hCG, show a
distinct juvenile period of silenced hypothala-
mus–pituitary–gonadal axis activity, and have dis-
tinct kinetics during spermatogenesis with more
transitional phases.
Equivalent to mice, case reports suggest that
completely inactivating mutations in LHß gene in
humans seem to arrest spermatogenesis [60–62].
However, spermatogenesis was successfully initiated
by hCG treatment or even testosterone alone in
some of the patients, suggesting a large enough
reserve of Sertoli cells and spermatogonia [60–62].
Mutations in LH receptors seem to result in a more
severe phenotype in human compared to mice,
because it is shared by LH and hCG during foetal
development [63]. In agreement with studies on
tfm mice, patients with 46,XY complete androgen
insensitivity syndrome due to inactivating AR
mutation have a female phenotype, do not progress
beyond spermatocytes in spermatogenesis, and are
infertile [64].
Homozygous inactivating mutations in human
in the FSHß-subunit result in infertility [65–68]. In
contrast, and analogous to mice, homozygous inac-
tivating FSHR mutation was associated with reduced
semen quality and testicular volume in men, but not
with infertility [69]. The FSHR mutation seems to
abolish downstream receptor function [63,70],
which is supported by poor response to recombinant
FSH treatment, despite the massive doses among
one man and two women with the FSHR mutation
220 www.co-endocrinology.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
[63,71]. Thus, the reason for the discrepancy in
spermatogenic capacity in men with FSHß versus
FSHR mutation remains open.
Further insights to the role of these hormones in
human testicular growth can be gained by exper-
imental studies in non-human primates. Precocious
administration of testosterone initiated testicular
growth and appearance of some spermatocytes
during 12 weeks in rhesus monkeys [72], and quali-
tatively complete spermatogenesis was noticed after
premature administration of testosterone for 12
months in crab-eating macaques [73]. This suggests
that, similar to mice, testosterone is sufficient to
initiate spermatogenesis in primates in principle.
However, the ejaculates obtained by electrostimu-
lation from the testosterone-treated crab-eating
macaques were too small to even allow the quanti-
fication of the sperm density, suggesting a poor
reproductive function [73]. This could be explained
by reduced number of spermatogonia entering
spermatogenesis.
In juvenile rhesus monkeys, precocious Sertoli
cell proliferation was achieved by pulsatile stimu-
lation with either FSH or LH already in 11 days,
whereas complete spermatogenesis was achieved
only with combined treatment during this short
study [74]. Results with combined treatment fit well
with the hypothesis that FSH facilitates the Sertoli
cell and spermatogonial development, thus reduc-
ing the time needed to reach complete spermato-
genesis [75].
There is evidence that FSH can further stimulate
spermatogenesis also in adult primates via Sertoli
cells. Hemicastration of adult Rhesus monkeys
increased germ cell numbers in the remaining testis
despite no changes in Sertoli cell number [30]. Cor-
relation between the two cell types was markedly
closer after hemicastration in that small study,
suggesting that the Sertoli cell number apparently
modulated the ability to increase germ cell numbers
[30]. This indicates that the spermatogenesis does
not normally run in maximal capacity allowed by
the Sertoli cells in primates. These changes were
paralleled with a sustained increase in FSH and
decrease in inhibin B [29,30], which acts as negative
feedback mechanism for FSH [76]. A later exper-
imental study from the same laboratory elucidated
that a comparable effect on germ cells and Sertoli
cells in adult Rhesus monkeys could be exerted by an
increase in pulse amplitude of FSH while maintain-
ing the LH pulse amplitude fixed, whereas the same
did not happen vice versa [31].
A study on men after undergoing orchiectomy
due to testicular cancer showed compensatory con-
tralateral testicular growth and increase in sperm
concentration and total count after the nadir
Volume 24  Number 3  June 2017

imposed by the orchiectomy, accompanied by com-
pensatory changes in FSH–inhibin B axis [32].
Furthermore, a randomized controlled trial observed
an increase in testicular volume after FSH treatment
for idiopathic male infertility [77], whereas in
another randomized study, this was evident only
after post-hoc division of treated patients based on
FSHR polymorphisms [78]. In terms of sperm pro-
duction or motility, results are more variable, but
suggest that FSH treatment may be beneficial for a
subset of men with oligozoospermia [79]. Finally, a
systematic Cochrane review found moderate evi-
dence for increased likelihood of pregnancy after
FSH treatment for male factor sub-fertility in random-
ized controlled studies with an odds ratio of 4.94 [80].
Thus, spermatogenesis may run below the Sertoli cell
carrying capacity also in humans.
We have summarized our view of testicular
growth in humans schematically in Fig. 4. Testicular
growth before and early during puberty is due to
Sertoli cell and spermatogonial proliferation, which
can be promoted by FSH. Peak in testicular growth is
mainly due to increase in meiotic and haploid germ
cells due to onset of spermatogenesis and is prim-
arily controlled by androgens. However, the peak
testicular growth may be augmented by FSH, and is
probably modulated by the effect of FSH on Sertoli
cell proliferation before the peak. After completion
of pubertal testicular growth, stimulation with FSH
can under some circumstances induce further sper-
matogonial proliferation and testicular growth.
INDUCTION OF TESTICULAR GROWTH
AND SPERMATOGENESIS IN
HYPOGONADOTROPIC HYPOGONADISM
Patients with hypogonadotropic hypogonadism
lack the secretion of both FSH and LH from
the hypothalamus–pituitary axis, and thus have
impaired or absent pubertal testicular growth, sper-
matogenesis, and secondary sex characteristics [81].
Therefore, clinical intervention studies on induc-
tion of testicular growth and spermatogenesis in
hypogonadotropic hypogonadism patients provide
a further basis to speculate the role of FSH and LH/
testosterone in humans. For a review focusing on
treatment of hypogonadotropic hypogonadism, we
recommend the excellent recent reviews by Boehm
et al. [81] and Dwyer et al. [82].
Men with hypogonadotropic hypogonadism are
treated either with pulsatile subcutaneous adminis-
tration of GnRH or repeated gonadotropin injec-
tions to induce fertility [81]. Many clinics favour
the latter for practical reasons. Commonly, the
mainstay of the gonadotropin treatment is injec-
tions with hCG, which was itself sufficient to induce
1752-296X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Testicular growth in puberty Koskenniemi et al.
FSH LH / T
FSH + LH/T
(LH/T) (FSH)
Spermatids
Testicular volume
Spermatocytes
Spermatogonia
Sertoli cells
Leydig cells
Age
FIGURE 4. Schematic representation of pubertal testicular
growth and likely distribution of testicular cell populations in
humans. Reproductive hormones responsible for most of the
growth during each timeframe are shown on top.
spermatogenesis among patients who showed evi-
dence of pubertal testicular growth [83]. Overall,
large baseline testicular volume predicts better
response to medical treatment among hypogonado-
tropic hypogonadism patients [84–86].
On the basis of the data reviewed above, it is
likely that these men had enough spermatogonial
and Sertoli cell proliferation during puberty to pro-
duce sperm, but spermatogenesis was not completed
due to lack of LH/testosterone action. However,
testosterone alone seems insufficient to initiate
[87,88] or fully maintain spermatogenesis even
when combined with FSH [88], at least in numbers
needed to produce sperm in ejaculate.
The treatment with hCG can be augmented by
FSH if there is no evidence of prior pubertal testic-
ular growth, or if patient responds poorly to hCG
alone. This promotes testicular growth, and
increases the likelihood to initiate spermatogenesis
and thus father a child [89,90]. A small study utiliz-
ing the Sertoli cell maturation marker AMH indi-
cated that Sertoli cell maturation takes place during
the combined gonadotropin treatment in patients
with hypogonadotropic hypogonadism [91]. This
and the studies reviewed above suggest that hCG
treatment, which increases the intra-testicular tes-
tosterone levels, promotes the cessation of Sertoli
cell proliferation, which is necessary for full sper-
matogenesis. Thus, testicular growth during isolated
www.co-endocrinology.com 221
Androgens
hCG treatment may be more due to germ cell than
Sertoli cell proliferation. However, this cannot be
definitely shown, because, to our knowledge, the
effect of hCG pre-treatment alone or in combi-
nation with successive FSH treatment has not been
evaluated by testicular biopsies.
An alternative sequential approach exploits
insights from Sertoli cell biology and aims to maxi-
mize the Sertoli cell number by administering FSH
alone, succeeded by the induction of puberty, sper-
matogonial proliferation, and completion of sper-
matogenesis by combined treatment with FSH and
hCG, or pulsatile administration of GnRH alone
[92–95]. The small study mentioned above showed
that circulating AMH levels increased during iso-
lated FSH pre-treatment, suggesting an increase in
Sertoli cell number [91]. This treatment regimen also
showed promising results in terms of restored
inhibin B values and testicular growth in case
reports [92,93] and in a retrospective patient series
[94].
Furthermore, a small randomized prospective
study showed that pre-treatment doubled the tes-
ticular volume and restored inhibin B values closer
to reference range, despite the lack of spermato-
genesis in testicular biopsies taken before the induc-
tion of puberty by pulsatile GnRH [95]. This
indicates that the testicular growth was due to Ser-
toli cell proliferation [96]. During the GnRH treat-
ment, FSH, inhibin B, and even LH seemed to reside
closer to normal in the small group of nine boys who
were randomized to pre-treatment, and all seven
participants who completed the study in pre-treat-
ment group produced sperm in the ejaculate com-
pared to 4/6 randomized to GnRH treatment alone
[95]. However, the differences were not statistically
significant, very likely due to small study size [95].
Although these results appear promising, larger
randomized controlled trials comparing this treat-
ment strategy to others are needed to assess whether
the prolonged use of FSH is justified.
CONCLUSION
Pubertal testicular growth follows sigmoidal curve
and is mostly due to increase in testicular cord
diameter caused by the expansion of germ cell
numbers. Late pre-pubertal FSH secretion seems to
stimulate Sertoli cell proliferation followed by
pubertal androgen surge that leads to Sertoli cell
maturation and onset of spermatogenesis. Sequen-
tial treatment with FSH succeeded by induction of
spermatogenesis seems promising in treatment of
hypogonadotropic hypogonadism based on exper-
imental and human data; however, its efficacy
remains to be proven.
222 www.co-endocrinology.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Acknowledgements
None.
Financial support and sponsorship
We thank the Academy of Finland, Sigrid Juselius
Foundation, Novo Nordisk Foundation, and Juvenile
Diabetes Research Foundation for financial support.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Cortes D, Müller J, Skakkebaek NE. Proliferation of Sertoli cells during
development of the human testis assessed by stereological methods. Int J
Androl 1987; 10:589–596.
2. Müller J, Skakkebaek NE. Quantification of germ cells and seminiferous
tubules by stereological examination of testicles from 50 boys who suffered
from sudden death. Int J Androl 1983; 6:143–156.
3. Hart RJ, Doherty DA, McLachlan RI, et al. Testicular function in a birth cohort
&& of young men. Hum Reprod 2015; 30:2713–2724.
A thorough analysis of predictors of testicular function in a large cohort men with an
exceptionally high participation rate.
4. Joustra SD, van der Plas EM, Goede J, et al. New reference charts for
testicular volume in Dutch children and adolescents allow the calculation of
standard deviation scores. Acta Paediatr 2015; 104:e271–e278.
5. Zachmann M, Prader A, Kind HP, et al. Testicular volume during adolescence.
Cross-sectional and longitudinal studies. Helv Paediatr Acta 1974; 29:
61–72.
6. Largo RH, Prader A. Pubertal development in Swiss boys. Helv Paediatr Acta
1983; 38:211–228.
7. Sadov S, Koskenniemi JJ, Virtanen HE, et al. Testicular growth during puberty
&& in boys with and without a history of congenital cryptorchidism. J Clin
Endocrinol Metab 2016; 101:2570–2577.
Our own longitudinal study showing that pubertal testicular growth pattern differs
between healthy and cryptorchid boys.
8. Sakamoto H, Saito K, Oohta M, et al. Testicular volume measurement:
comparison of ultrasonography, orchidometry, and water displacement. Ur-
ology 2007; 69:152–157.
9. Bland JM, Altman DG. Statistical methods for assessing agreement between
two methods of clinical measurement. Lancet (London, England) 1986;
1:307–310.
10. Diamond DA, Paltiel HJ, DiCanzio J, et al. Comparative assessment of
pediatric testicular volume: orchidometer versus ultrasound. J Urol 2000;
164:1111–1114.
11. Sakamoto H, Saito K, Ogawa Y, Yoshida H. Testicular volume measurements
using prader orchidometer versus ultrasonography in patients with infertility.
Urology 2007; 69:158–162.
12. Schiff JD, Li PS, Goldstein M. Correlation of ultrasonographic and orchid-
ometer measurements of testis volume in adults. BJU Int 2004; 93:1015–
1017.
13. Goede J, Hack WWM, Sijstermans K, et al. Normative values for testicular
volume measured by ultrasonography in a normal population from infancy to
adolescence. Horm Res Paediatr 2011; 76:56–64.
14. Taskinen S, Taavitsainen M, Wikstrom S. Measurement of testicular volume:
comparison of 3 different methods. J Urol 1996; 155:930–933.
15. Lenz S, Giwercman A, Elsborg A, et al. Ultrasonic testicular texture and size in
444 men from the general population: correlation to semen quality. Eur Urol
1993; 24:231–238.
16. Rastrelli G, Corona G, Lotti F, et al. Relationship of testis size and LH levels
with incidence of major adverse cardiovascular events in older men with
sexual dysfunction. J Sex Med 2013; 10:2761–2773.
17. Biro FM, Lucky AW, Huster GA, Morrison JA. Pubertal staging in boys. J
Pediatr 1995; 127:100–102.
18. Lawaetz JG, Hagen CP, Mieritz MG, et al. Evaluation of 451 Danish boys with
& delayed puberty: diagnostic use of a new puberty nomogram and effects of
oral testosterone therapy. J Clin Endocrinol Metab 2015; 100:1376–1385.
Danish study pioneering a puberty nomogram that can be used to track pubertal
development based on Tanner stage or testicular volume by orchidometer.
19. Semiz S, Kurt F, Kurt DT, et al. Pubertal development of Turkish children.
J Pediatr Endocrinol Metab 2008; 21:951–961.
Volume 24  Number 3  June 2017

20. Sørensen K, Aksglaede L, Petersen JH, Juul A. Recent changes in pubertal
timing in healthy Danish boys: associations with body mass index. J Clin
Endocrinol Metab 2010; 95:263–270.
21. Matsuo N, Anzo M, Sato S, et al. Testicular volume in Japanese boys up to the
age of 15 years. Eur J Pediatr 2000; 159:843–845.
22. Saari A, Sankilampi U, Hannila M-L, et al. New Finnish growth references for
children and adolescents aged 0 to 20 years: length/height-for-age, weight-
for-length/height, and body mass index-for-age. Ann Med 2011; 43:235–
248.
23. Tinggaard J, Mieritz MG, Sørensen K, et al. The physiology and timing of male
puberty. Curr Opin Endocrinol Diabetes Obes 2012; 19:197–203.
24. Rey RA, Campo SM, Bedecarrás P, et al. Is infancy a quiescent period of
testicular development? Histological, morphometric, and functional study of
the seminiferous tubules of the cebus monkey from birth to the end of puberty.
J Clin Endocrinol Metab 1993; 76:1325–1331.
25. Marshall GR, Plant TM. Puberty occurring either spontaneously or induced
precociously in rhesus monkey (Macaca mulatta) is associated with a marked
proliferation of Sertoli cells. Biol Reprod 1996; 54:1192–1199.
26. Simorangkir DR, Marshall GR, Plant TM. Sertoli cell proliferation during
prepubertal development in the rhesus monkey (Macaca mulatta) is maximal
during infancy when gonadotropin secretion is robust. J Clin Endocrinol
Metab 2003; 88:4984–4989.
27. Simorangkir DR, Ramaswamy S, Marshall GR, et al. Sertoli cell differentiation
in rhesus monkey (Macaca mulatta) is an early event in puberty and precedes
attainment of the adult complement of undifferentiated spermatogonia. Re-
production 2012; 143:513–522.
28. Orth JM, Gunsalus GL, Lamperti AA. Evidence from sertoli cell-depleted rats
indicates that spermatid number in adults depends on numbers of sertoli cells
produced during perinatal development. Endocrinology 1988; 122:787–
794.
29. Ramaswamy S, Marshall GR, McNeilly AS, Plant TM. Evidence that in a
physiological setting Sertoli cell number is the major determinant of circulating
concentrations of inhibin B in the adult male rhesus monkey (Macaca mulatta).
J Androl 1999; 20:430–434.
30. Ramaswamy S, Marshall GR, Mcneilly AS, Plant TM. Dynamics of the follicle-
stimulating hormone (FSH)-inhibin B feedback loop and its role in regulating
spermatogenesis in the adult male rhesus monkey (Macaca mulatta) as
revealed by unilateral orchidectomy. Endocrinology 2000; 141:18–27.
31. Simorangkir DR, Ramaswamy S, Marshall GR, et al. A selective monotropic
elevation of FSH, but not that of LH, amplifies the proliferation and differentia-
tion of spermatogonia in the adult rhesus monkey (Macaca mulatta). Hum
Reprod 2009; 24:1584–1595.
32. Selice R, Ferlin A, Garolla A, et al. Effects of endogenous FSH on normal
human spermatogenesis in adults. Int J Androl 2011; 34:511–517.
33. Sharpe RM, McKinnell C, Kivlin C, Fisher JS. Proliferation and functional
maturation of Sertoli cells, and their relevance to disorders of testis function in
adulthood. Reproduction 2003; 125:769–784.
34. Tarulli GA, Stanton PG, Meachem SJ. Is the adult Sertoli cell terminally
differentiated? Biol Reprod 2012; 87 (13):1–11.
35. Aksglaede L, Sørensen K, Boas M, et al. Changes in anti-Müllerian hormone
(AMH) throughout the life span: a population-based study of 1027 healthy
males from birth (cord blood) to the age of 69 years. J Clin Endocrinol Metab
2010; 95:5357–5364.
36. Chemes HE, Rey RA, Nistal M, et al. Physiological androgen insensitivity of
the fetal, neonatal, and early infantile testis is explained by the ontogeny of the
androgen receptor expression in sertoli cells. J Clin Endocrinol Metab 2008;
93:4408–4412.
37. Rey RA, Musse M, Venara M, Chemes HE. Ontogeny of the androgen
receptor expression in the fetal and postnatal testis: its relevance on sertoli
cell maturation and the onset of adult spermatogenesis. Microsc Res Tech
2009; 72:787–795.
38. Rajpert-De Meyts E, Jørgensen N, Graem N, et al. Expression of anti-Müllerian
hormone during normal and pathological gonadal development: association
with differentiation of Sertoli and granulosa cells. J Clin Endocrinol Metab
1999; 84:3836–3844.
39. Rey R, Lordereau-Richard I, Carel JC, et al. Antimüllerian hormone and
testosterone serum levels are inversely related during normal and precocious
pubertal development. J Clin Endocrinol Metab 1993; 77:1220–1226.
40. Rey R, Mebarki F, Forest MG, et al. Antimüllerian hormone in children with
androgen insensitivity. J Clin Endocrinol Metab 1994; 79:960–964.
41. Rey R, Al-Attar L, Louis F, et al. Testicular dysgenesis does not affect
expression of antimüllerian hormone by Sertoli cells in premeiotic seminifer-
ous tubules. Am J Pathol 1996; 148:1689–1698.
42. Al-Attar L, Noël K, Dutertre M, et al. Hormonal and cellular regulation of Sertoli
cell anti-Müllerian hormone production in the postnatal mouse. J Clin Invest
1997; 100:1335–1343.
43. O’Shaughnessy PJ, Monteiro A, Abel M. Testicular development in mice
lacking receptors for follicle stimulating hormone and androgen. PLoS One
2012; 7:1–9.
44. Johnston H, Baker PJ, Abel M, et al. Regulation of Sertoli cell number and
activity by follicle-stimulating hormone and androgen during postnatal devel-
opment in the mouse. Endocrinology 2004; 145:318–329.
1752-296X Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Testicular growth in puberty Koskenniemi et al.
45. Abel MH, Baker PJ, Charlton HM, et al. Spermatogenesis and sertoli cell
activity in mice lacking sertoli cell receptors for follicle-stimulating hormone
and androgen. Endocrinology 2008; 149:3279–3285.
46. Lyon MF, Hawkes SG. X-linked gene for testicular feminization in the mouse.
Nature 1970; 227:1217–1219.
47. Singh J, O’Neill C, Handelsman DJ. Induction of spermatogenesis by andro-
gens in gonadotropin-deficient (hpg) mice. Endocrinology 1995; 136:5311–
5321.
48. De Gendt K, Swinnen JV, Saunders PTK, et al. A Sertoli cell-selective
knockout of the androgen receptor causes spermatogenic arrest in meiosis.
Proc Natl Acad Sci U S A 2004; 101:1327–1332.
49. Kaftanovskaya EM, Huang Z, Barbara AM, et al. Cryptorchidism in mice with
an androgen receptor ablation in gubernaculum testis. Mol Endocrinol 2012;
26:598–607.
50. Tan KAL, De Gendt K, Atanassova N, et al. The role of androgens in sertoli cell
proliferation and functional maturation: Studies in mice with total or sertoli cell-
selective ablation of the androgen receptor. Endocrinology 2005;
146:2674–2683.
51. De Gendt K, Atanassova N, Tan K, et al. Development and function of the adult
generation of Leydig cells in mice with Sertoli cell-selective or total ablation of
the androgen receptor. Endocrinology 2005; 146:4117–4126.
52. Chang C, Chen Y-T, Yeh S-D, et al. Infertility with defective spermatogenesis
and hypotestosteronemia in male mice lacking the androgen receptor in
Sertoli cells. Proc Natl Acad Sci U S A 2004; 101:6876–6881.
53. Welsh M, Saunders PTK, Atanassova N, et al. Androgen action via testicular
peritubular myoid cells is essential for male fertility. FASEB J 2009; 23:4218–
4230.
54. Xu Q, Lin H-Y, Yeh S-D, et al. Infertility with defective spermatogenesis and
steroidogenesis in male mice lacking androgen receptor in Leydig cells.
Endocrine 2007; 32:96–106.
55. Hazra R, Upton D, Desai R, et al. Elevated expression of the Sertoli cell
& androgen receptor disrupts male fertility. Am J Physiol Endocrinol Metab
2016; 311:E396–E404.
An interesting study in mice model showing that premature and excessive andro-
gen action during has adverse effects on spermatogenesis.
56. Zhang F-P, Pakarainen T, Zhu F, et al. Molecular characterization of postnatal
development of testicular steroidogenesis in luteinizing hormone receptor
knockout mice. Endocrinology 2004; 145:1453–1463.
57. Zhang FP, Poutanen M, Wilbertz J, Huhtaniemi I. Normal prenatal but arrested
postnatal sexual development of luteinizing hormone receptor knockout
(LuRKO) mice. Mol Endocrinol 2001; 15:172–183.
58. Singh J, Handelsman DJ. Neonatal administration of FSH increases Sertoli
cell numbers and spermatogenesis in gonadotropin-deficient (hpg) mice. J
Endocrinol 1996; 151:37–48.
59. Haywood M, Spaliviero J, Jimemez M, et al. Sertoli and germ cell development
in hypogonadal (hpg) mice expressing transgenic follicle-stimulating hormone
alone or in combination with testosterone. Endocrinology 2003; 144:509–
517.
60. Lofrano-Porto A, Barra GB, Giacomini LA, et al. Luteinizing hormone beta
mutation and hypogonadism in men and women. N Engl J Med 2007;
357:897–904.
61. Valdes-Socin H, Salvi R, Daly AF, et al. Hypogonadism in a patient with a
mutation in the luteinizing hormone beta-subunit gene. N Engl J Med 2004;
351:2619–2625.
62. Achard C, Courtillot C, Lahuna O, et al. Normal spermatogenesis in a man
with mutant luteinizing hormone. N Engl J Med 2009; 361:1856–1863.
63. Huhtaniemi IT, Themmen APN. Mutations in human gonadotropin and gona-
dotropin-receptor genes. Endocrine 2005; 26:207–217.
64. Hannema SE, Scott IS, Rajpert-De Meyts E, et al. Testicular development in
the complete androgen insensitivity syndrome. J Pathol 2006; 208:518–527.
65. Layman LC, Porto ALA, Xie J, et al. FSH beta gene mutations in a female with
partial breast development and a male sibling with normal puberty and
azoospermia. J Clin Endocrinol Metab 2002; 87:3702–3707.
66. Phillip M, Arbelle JE, Segev Y, Parvari R. Male hypogonadism due to a
mutation in the gene for the beta-subunit of follicle-stimulating hormone. N
Engl J Med 1998; 338:1729–1732.
67. Lindstedt G, Nyström E, Matthews C, et al. Follitropin (FSH) deficiency in an
infertile male due to FSHbeta gene mutation. A syndrome of normal puberty
and virilization but underdeveloped testicles with azoospermia, low FSH but
high lutropin and normal serum testosterone concentrations. Clin Chem Lab
Med 1998; 36:663–665.
68. Lofrano-Porto A, Casulari LA, Nascimento PP, et al. Effects of follicle-stimu-
lating hormone and human chorionic gonadotropin on gonadal steroidogen-
esis in two siblings with a follicle-stimulating hormone beta subunit mutation.
Fertil Steril 2008; 90:1169–1174.
69. Tapanainen JS, Aittomäki K, Min J, et al. Men homozygous for an inactivating
mutation of the follicle-stimulating hormone (FSH) receptor gene present
variable suppression of spermatogenesis and fertility. Nat Genet 1997;
15:205–206.
70. Rannikko A, Pakarinen P, Manna PR, et al. Functional characterization of the
human FSH receptor with an inactivating Ala189Val mutation. Mol Hum
Reprod 2002; 8:311–317.
www.co-endocrinology.com 223
Androgens
71. Vaskivuo TE, Aittomäki K, Anttonen M, et al. Effects of follicle-stimulating
hormone (FSH) and human chorionic gonadotropin in individuals with an
inactivating mutation of the FSH receptor. Fertil Steril 2002; 78:108–113.
72. Arslan M, Weinbauer GF, Schlatt S, et al. FSH and testosterone, alone or in
combination, initiate testicular growth and increase the number of sperma-
togonia and Sertoli cells in a juvenile nonhuman primate (Macaca mulatta). J
Endocrinol 1993; 136:235–243.
73. Marshall GR, Wickings EJ, Nieschlag E. Testosterone can initiate spermato-
genesis in an immature nonhuman primate, Macaca fascicularis. Endocrinol-
ogy 1984; 114:2228–2233.
74. Ramaswamy S, Plant TM, Marshall GR. Pulsatile stimulation with recombinant
single chain human luteinizing hormone elicits precocious sertoli cell prolif-
eration in the juvenile male rhesus monkey (Macaca mulatta). Biol Reprod
2000; 63:82–88.
75. Plant TM, Marshall GR. The functional significance of FSH in spermatogen-
esis and the control of its secretion in male primates. Endocr Rev 2001;
22:764–786.
76. de Kretser DM, Buzzard JJ, Okuma Y, et al. The role of activin, follistatin and
inhibin in testicular physiology. Mol Cell Endocrinol 2004; 225:57–64.
77. Kamischke A, Behre HM, Bergmann M, et al. Recombinant human follicle
stimulating hormone for treatment of male idiopathic infertility: a randomized,
double-blind, placebo-controlled, clinical trial. Hum Reprod 1998; 13:596–
603.
78. Selice R, Garolla A, Pengo M, et al. The response to FSH treatment in
oligozoospermic men depends on FSH receptor gene polymorphisms. Int J
Androl 2011; 34:306–312.
79. Valenti D, La Vignera S, Condorelli RA, et al. Follicle-stimulating hormone
treatment in normogonadotropic infertile men. Nat Rev Urol 2013; 10:55–62.
80. Attia AM, Abou-Setta AM, Al-Inany HG. Gonadotrophins for idiopathic male
factor subfertility. Cochrane Database Syst Rev 2013; 8:CD005071.
81. Boehm U, Bouloux P, Dattani MT, et al. Expert consensus document:
European Consensus Statement on congenital hypogonadotropic hypogo-
nadism: pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2015;
11:547–564.
82. Dwyer AA, Raivio T, Pitteloud N. Gonadotrophin replacement for induction of
fertility in hypogonadal men. Best Pract Res Clin Endocrinol Metab 2015;
29:91–103.
83. Burris AS, Rodbard HW, Winters SJ, Sherins RJ. Gonadotropin therapy in
men with isolated hypogonadotropic hypogonadism: the response to human
chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol
Metab 1988; 66:1144–1151.
84. Liu PY, Baker HWG, Jayadev V, et al. Induction of spermatogenesis and
fertility during gonadotropin treatment of gonadotropin-deficient infertile men:
predictors of fertility outcome. J Clin Endocrinol Metab 2009; 94:801–808.
224 www.co-endocrinology.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
85. Warne DW, Decosterd G, Okada H, et al. A combined analysis of data to
identify predictive factors for spermatogenesis in men with hypogonadotropic
hypogonadism treated with recombinant human follicle-stimulating hormone
and human chorionic gonadotropin. Fertil Steril 2009; 92:594–604.
86. Büchter D, Behre HM, Kliesch S, Nieschlag E. Pulsatile GnRH or human
chorionic gonadotropin/human menopausal gonadotropin as effective treat-
ment for men with hypogonadotropic hypogonadism: a review of 42 cases.
Eur J Endocrinol 1998; 139:298–303.
87. Yang L, Zhang SX, Dong Q, et al. Application of hormonal treatment in
hypogonadotropic hypogonadism: more than ten years experience. Int Urol
Nephrol 2012; 44:393–399.
88. Schaison G, Young J, Pholsena M, et al. Failure of combined follicle-stimulat-
ing hormone-testosterone administration to initiate and/or maintain sperma-
togenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol
Metab 1993; 77:1545–1549.
89. Matsumoto AM, Snyder PJ, Bhasin S, et al. Stimulation of spermatogenesis
with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-
f): long-term treatment in azoospermic men with hypogonadotropic hypogo-
nadism. Fertil Steril 2009; 92:979–990.
90. Zacharin M, Sabin MA, Nair VV, Dagabdhao P. Addition of recombinant
follicle-stimulating hormone to human chorionic gonadotropin treatment in
adolescents and young adults with hypogonadotropic hypogonadism pro-
motes normal testicular growth and may promote early spermatogenesis.
Fertil Steril 2012; 98:836–842.
91. Young J, Chanson P, Salenave S, et al. Testicular antimullerian hormone
secretion is stimulated by recombinant human FSH in patients with congenital
hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2005; 90:724–
728.
92. Raivio T, Toppari J, Perheentupa A, et al. Treatment of prepubertal gonado-
trophin-deficient boys with recombinant human follicle-stimulating hormone.
Lancet (London, England) 1997; 350:263–264.
93. Main K M, Schmidt I M, Toppari J, Skakkebaek N E. Early postnatal treatment
of hypogonadotropic hypogonadism with recombinant human FSH and LH.
Eur J Endocrinol 2002; 146:75–79.
94. Raivio T, Wikström AM, Dunkel L. Treatment of gonadotropin-deficient boys
with recombinant human FSH: long-term observation and outcome. Eur J
Endocrinol 2007; 156:105–111.
95. Dwyer AA, Sykiotis GP, Hayes FJ, et al. Trial of recombinant follicle-stimulating
hormone pretreatment for GnRH-induced fertility in patients with congenital
hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2013; 98:
E1790–E1795.
96. Andersson AM, Müller J, Skakkebaek NE. Different roles of prepubertal and
postpubertal germ cells and Sertoli cells in the regulation of serum inhibin B
levels. J Clin Endocrinol Metab 1998; 83:4451–4458.
Volume 24  Number 3  June 2017