Congenital Micropenis Etiology and Management

Congenital Micropenis: Aetiology And Management
Marianna Rita Stancampiano1, Kentaro Suzuki2, Stuart O’Toole3, Gianni Russo1, Gen Yamada2, Syed
Faisal Ahmed4
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1- Department of Pediatrics, Endocrine Unit, Scientific Institute San Raffaele, Milan, Italy
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2- Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical
University, Wakayama, Japan
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3- Department of Paediatric Surgery and Urology, Royal Hospital for Children, Glasgow, UK
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4- Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK.
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Corresponding Author
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Professor S. Faisal Ahmed, MD FRCPCH,
Developmental Endocrinology Research Group,

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School of Medicine, Dentistry & Nursing, University of Glasgow,

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Office Block, Royal Hospital for Children,

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1345 Govan Road,
Glasgow G51 4TF, UK

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[email protected]
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Disclosure statement: Authors have nothing to declare.
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine
Society.
This is an Open Access article distributed under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-
nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any
medium, provided the original work is not altered or transformed in any way, and that the
work is properly cited. For commercial re-use, please contact [email protected]
Abstract
In the newborn, penile length is determined by a number of androgen dependent and independent
factors. The current literature suggests that there are inter-racial differences in stretched penile
length in the newborn and although congenital micropenis should be defined as a stretched penile

length of less than 2.5SDS of the mean for the corresponding population and gestation, a pragmatic
approach would be to evaluate all boys with a stretched penile length below 2 cm, as congenital
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micropenis can be a marker for a wide range of endocrine conditions. However, it remains unclear
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as to whether the state of micropenis, itself, is associated with any long-term consequences. There
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is a lack of systematic studies comparing the impact of different therapeutic options on long-term
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outcomes, in terms of genital appearance, quality of life and sexual satisfaction. To date, research
has been hampered by a small sample size and inclusion of a wide range of heterogeneous
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diagnoses; for these reasons, condition specific outcomes have been difficult to compare between
studies. Lastly, there is a need for a greater collaborative effort in collecting standardized data so
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that all real-world or experimental interventions performed at an early age can be studied
systematically into adulthood.

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Keywords: Micropenis, testosterone, gonadotropins, DSD.

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2
Introduction

The term congenital micropenis is used in clinical practice to refer to a penis that is shorter than
expected for a newborn male infant (1). Given that length is a continuum, the definition of a
micropenis is relatively arbitrary. However, the identification of a micropenis is important as it may
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indicate an underlying health condition that requires further investigation. Congenital micropenis
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may be associated with psychosocial distress in parents (2) and although it is reported that young
adults with this condition may suffer from a poorer quality of life (3–5), this finding is not universal
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(6). Often, the initial evaluation and management of congenital micropenis has involved the
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administration of androgens to the young infant with a view to enlarging the penile size. However,
the effectiveness of this therapy, especially as far as long-term outcome goes, remains questionable.
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It is expected that a clearer understanding of penile development, normal variations, the
pathophysiology of micropenis as well as standardized long-term follow-up will improve this

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condition’s management. This review will cover these aspects and identify areas for future research.
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Development of the penis

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Penile development is a complex multistep process. Whilst the role of androgens in the
masculinization of the external genitalia is indisputable, there are specific aspects of penile
development that are also dependent on factors other than androgens (6). The human penis
develops from the genital tubercle (GT), an elevation of the perineum, already recognizable at 5-6
weeks of gestation as a pair of buds, the genital swellings, on the either side of the cloacal
membrane (7,8). Signalling through Fgf (Fibroblast growth factor), Wnt (Wingless related integration
site) and Shh (Sonic hedgehog) has been recently identified in the initiation and maintenance of
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genital budding and their concerted action may be critical for preparing mesenchymal competency for
androgen action (7,9). Wnt/β-catenin signaling has been implicated in the regulation of multiple
developmental processes such as cell proliferation, differentiation and cell migration. Activation of
the β-catenin signaling pathway is necessary for GT masculinization (9). The critical role of this
pathway is further supported by the finding that genetically modified female mice with

constitutively activated β-catenin signaling show male-type external genitalia. In addition, Dkk2
(Dickkopf-related protein 2), that encodes an extracellular antagonist of canonical Wnt/β-catenin
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signaling, is highly expressed in female GT mesenchyme (Fig. 1). In the male GT, Dkk2 is regulated
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negatively by the androgen receptor (AR) which plays a transcriptional repressor role by modulating
histone methylation via recruitment of LSD1 (lysine-specific histone demethylase 1) (10) (Fig. 1).
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There is further experimental evidence in the mouse, that androgen-induced genes that are responsible
for masculinization of the external genitalia may be epigenetically regulated by SP1 (Specificity
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protein 1), a ubiquitously expressed transcription factor that regulates a range of house-keeping and
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tissue-specific genes (11) (Fig. 1). It is also possible that there are some master regulating genes, such
as AP-1 (Activator protein 1), that also play a critical role in modulating genital development and
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identification of these will provide further insight into future therapeutic strategies for micropenis
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(12).
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In humans, the GT contains tissue derived from all 3 germ layers: the ectoderm, from which the skin
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of phallus and prepuce will develop; the mesoderm, from which the corporal bodies will develop;
and, the endoderm, forming the urethral plate, which will give rise to the penile urethra (13). In
humans, before the 10th week of gestation, the GT in males and females appears identical in size and
morphology (14,15). At about 9-10 weeks of gestation, when gonadal differentiation of the
bipotential gonad has begun, the urethral plate begins to canalize, forming a wide diamond-shaped
groove on the ventral surface of the male genital tubercle. The lateral urethral folds of the groove
then fuse in the ventral midline, creating the tubular urethra within the penile shaft (15,16). At this
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stage, testosterone and dihydrotestosterone (DHT) play a key role through their action on the AR,
expressed in the epithelium and mesenchyme of the urethral folds (17,18). From 8 to 18 weeks of
gestation, penile length significantly increases from 0.5 mm to 8 mm in humans (19). This period
corresponds to the increased production of testosterone by fetal testis, documented as 150-400
ng/dl (5.2-13.9 nmol/l) (6,17). After that, fetal testosterone production decreases, remaining stable

at less than 100 ng/dl (3.5 nmol/l) until birth (6,17). However, between 20 weeks of gestation and
birth, the penis may grow an additional 2 cm, before reaching its full newborn length (15,16). Thus,
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penile growth in humans is strictly regulated by androgens during the early weeks of gestation, at
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the time of minipuberty and during puberty; however, other hormonal pathways may contribute to
penile growth from 20 weeks of gestation until the point of minipuberty and from 6-8 months of age
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until puberty (15,19). Several reports have suggested that growth hormone and IGF1 may be
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involved in penile growth (6,20). Moreover, in healthy term newborns, penile length has been shown
to correlate to other markers of prenatal androgenisation such as anogenital distance (21), and
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penile length may also show an association to birth length (22), highlighting the overlapping role
played by determinants of skeletal and genital development.

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Environment & Epidemiology

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The detrimental effect of environmental prenatal exposure to endocrine disruptors on the
androgenisation of male offspring has been described for over three decades now (23,24). This has
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also been supported by other observations such as the reports of micropenis in cases of prenatal
maternal use of antifungals (25,26), as well as a reported association between exposure to
endocrine disruptor chemicals and micropenis (27–29). However, the association between maternal
exposure to endocrine disruptors when assessed by measurement of antenatal urinary
concentrations of phtalates and related chemicals has not shown this same relationship (30,31).
Furthermore, the stretched penile length (SPL) in male newborns has not shown a temporal
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reduction over the last seven decades (Table 1) (22,32-36,38,40–57). Notably, the reports from the
US from the 1970s and most recently in 2021 document a similar SPL (22,32,57) as does a study
performed in South Korea which compared newborn SPL over two temporal periods 25 years apart
(41). This observation of a lack of a temporal association to a change in penile length is contrary to
the reports of increasing birth prevalence of other conditions that may be associated with a

disruption in androgen exposure, such as hypospadias and cryptorchidism (23,58).
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Identification of a micropenis
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Micropenis has to be differentiated from buried, webbed or trapped penis. In the webbed penile
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anomaly, the scrotal sac extends onto the ventral aspect of the penile shaft, giving the visual
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appearance of a small penis, but palpation of the corpora will reveal the true state. In approximately
3-4% of newborns, the shaft of the penis may be buried within the peripubic fat (39), and this is
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commoner in older and particularly overweight boys. A trapped penis refers to a penis that has
become entrapped by scar tissues or excessive excision of preputial or shaft skin following an
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intervention such as a circumcision. Other associated penile malformations include chordee when
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the penis is curved and this can give an impression of a micropenis. It follows that prior to
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measurement of the penile length, there is a need for a careful examination of the penis and the rest
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of the genitalia. Penile length should be measured as SPL: the suprapubic fat should be pressed
inwards as much as possible, the foreskin must be retracted and the glans penis should be held with
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the thumb and forefinger; then, the measurement should be taken from the pubis to the distal tip of
the glans penis, over the dorsal side (59,60). The SPL that is measured in the newborn within the
first 12 hours of life has been reported to be 10% shorter than the true SPL and may thus require re-
assessment (39). The inter-observer and intra-observer variation for trained personnel has been
reported as standard deviation (SD) and 1SD is 0.34 cm and 0.18 cm, respectively (47). Another
measurement technique that has been described uses a modified 10 ml syringe in which the penis is
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stretched during the suction (61). It is possible that this method may reduce the measurement
variability which is introduced by the suprapubic fat (60) but this requires further study. Since the
first report by Schonfeld and Beebe in 1942 (32), several studies have reported normal values of SPL
for newborn full-term male infants (Table 1) and pre and post-pubertal boys, related to age, Tanner
stages and ethnicities (22,32-36,38,40-57). For Caucasian preterm infants born at 24-36 weeks’

gestation, Tuladhar et.al proposed that normal values of SPL could be calculated using the formula:
(0.16 x weeks of gestation) -2.27 (44).
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Micropenis is defined as a normally formed penis with a SPL which is less than 2.5 SDS below the
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mean for the patient’s age (59) and ethnicity (45). In term newborns, micropenis may be defined as
a SPL of less than 1.5 cm in Japan and Mexico, 1.8 cm in Europe and 2.7 cm in Brazil (Table 1). Based
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on these data, perhaps 2 cm may represent a more appropriate cut-off as an international standard
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whilst bearing in mind the regional and genetic differences (Fig. 2). Recently, some studies have also
reported measurements of penile circumference for preterm and term neonates (54), but this has
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not been regularly measured when assessment is undertaken for micropenis.

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Aetiology
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Micropenis may present as an isolated genital condition, it may present with other abnormalities of
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the genitalia such as undescended testes, hypospadias, bifid scrotal folds or it may be one of several
features of a congenital syndrome with multisystem abnormalities (59). Endocrine causes of
micropenis can be attributed to a defect of the hypothalamic-pituitary-gonadal axis (congenital
hypogonadotropic hypogonadism) (62) that may present alone or in combination with inadequate or
absent production of other anterior pituitary hormones (congenital hypopituitarism) (63). Multiple
pituitary hormone deficiencies may also be part of a syndromic spectrum, such as Prader-Willi
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syndrome (64), Bardet-Biedl syndrome (65), Laurence-Moon syndrome (66), Charge syndrome (67),
Silver Russel syndrome (68) and Rud’s syndrome (69). Micropenis that is present as an isolated
feature or present in combination with other uro-genital anomalies, may also point towards a wide
range of disorders of sex development (DSD) (70). Moreover, micropenis has been described in
many genetic syndromes, including those caused by autosomal or sex chromosomal aneuploidies

such as trisomies 8,13,18 and 21 or poly-X syndromes, such as Klinefelter syndrome (71) and 49
XXXXY (72) (Table 2). Micropenis can also be a presenting feature of hypogonadism in men; for
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instance, in Klinefelter syndrome, 10-25% of men may have micropenis (73,74).
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The evaluation of an infant with micropenis
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Infants with micropenis, isolated or associated with atypical genitalia, need to be considered for
clinical, genetic and endocrine evaluation by a specialized multidisciplinary team (75). Although
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micropenis is instinctively considered to be an exclusively male condition, it is important to bear in
mind that 46, XX infants and children with a disorder of androgen excess such as congenital adrenal
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hyperplasia may present as an apparent boy with micropenis and bilateral undescended testis (76).
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In newborn girls, the length of the clitoris does not seem to be dependent on gestation and a
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newborn with a clitoral length greater than 8mm requires further evaluation (60). Micropenis,
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isolated or combined with other urogenital anomalies (hypospadias, undescended testes,
malformation of the scrotum) may be related to a range of endocrine disorders and differential
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diagnosis may be really challenging. The coexistence of neonatal metabolic or neurological
anomalies (such as neonatal hypoglycemia, prolonged jaundice, hypotonia) and/or dysmorphic
features needs to be considered to exclude concomitant absent production of other anterior
pituitary hormones (congenital hypopituitarism) and/or syndromic diseases, mentioned above. In
boys with micropenis with additional concerns about short stature or growth retardation, the
threshold for evaluating the GH axis should be lowered. Given that the aetiology of micropenis
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includes a wide range of conditions associated with DSD, children with isolated micropenis who do
not have hypogonadotropic hypogonadism (HH), isolated or combined with other anterior pituitary
hormone deficiencies, should also undergo a careful evaluation for DSD (75). When congenital
hypogonadotropic hypogonadism (CHH) is suspected, measurement of LH, FSH and testosterone in
early infancy and especially between 1 and 3 months of age may be helpful to catch the minipuberty

surge, before these hormones decline until the beginning of puberty (77). However, low
concentrations of gonadotropins or sex steroids have little diagnostic utility and need to be followed
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by dynamic stimulation tests including a LHRH stimulation test and a hCG stimulation test. The
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results of these dynamic tests in boys with possible CHH need to be interpreted carefully as a normal
LHRH stimulation test may not necessarily exclude CHH (78) and a poor testosterone rise following
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hCG stimulation is not uncommon in CHH (79). It is possible that a more prolonged hCG test that
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consists of the standard hCG test, followed by further 2 injections per week, for the following 2
weeks, with blood sample collected the day after the last injection may be more appropriate in such
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cases but this requires further study (80). Serum AMH and Inhibin B are also likely to be low in those
with CHH (81) but given that they may also be low in disorders of gonadal development, the results
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need to be interpreted in combination with the results of the other endocrine investigations. The
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additional clinical utility of INSL3 as a biochemical marker of hypogonadotropic hypogonadism

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requires further exploration (82).

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In cases that are suspected to have a DSD, abdomen ultrasound or MRI are useful for detecting the
Müllerian structures and to visualize the testes in case of abdominal cryptorchidism (83). However,
these tools are operator dependent and may also depend on the state of the child and the results
need to be interpreted cautiously and in combination with the results of the other investigations.
MRI of the brain including the pituitary and the olfactory tracts should be performed in cases of
suspected hypogonadotropic hypogonadism (84,85). Increasingly, diagnostic genetics utilize high
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throughput sequencing (HTS) or whole exome/genome sequencing (WEGS) for analysing panels of
candidate genes and given the wide range of causes of micropenis, detailed molecular genetic
analysis will be guided by the results of the clinical evaluation and may require a panel that includes
genes that are implicated in DSD and hypogonadotropic hypogonadism. Molecular genetic analysis
should be accompanied by a microarray to identify copy number variation especially in those cases

where there are associated extra-genital features (86). In centres with greater access to HTS or
WGES, it is possible that in the diagnostic pathway, genetic testing may be performed at an earlier
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stage than the more physically demanding dynamic endocrine investigations mentioned above. It is
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also increasingly becoming clear that even some of the screening tests such as AMH and Inhibin B
may be normal in genetically confirmed cases of congenital hypogonadotropic hypogonadism (87).
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Thus, the clinician may need to consider having a very low threshold for genetic investigation in
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cases of isolated micropenis.
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Hormonal Management Of Micropenis

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The main goal of treatment in boys with micropenis has usually been based on increasing the penile
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length with an assumption that it leads to an increase in self-esteem and body image of the boy
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whilts reassuring the parents of the newborn infant. In those cases that are suspected to have a DSD,
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this form of therapy may also allow the capacity to assess androgen responsiveness. Therapy with
sex hormones can be broadly divided into androgen therapy or gonadotropin therapy and
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establishing the aetiology of micropenis would be helpful before therapy is envisaged. Whilst several
reports exist on androgen and gonadotropin therapy for micropenis and these will be discussed in
more detail later, there remains a paucity of evidence of their long-term efficacy in improving SPL. A
recent report suggested that irrespective of the severity of the micropenis and whether hormonal
therapy is administered or not, in those with normal gonadal function, SPL shows an increase at
puberty and this improvement is greatest in those with shortest age-matched SPL (88). In those
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where the micropenis is associated with an endocrine disorder, the results on long-term outcome
are quite mixed with one study reporting that long-term SPL may not show an increase despite early
stage hormone therapy (89) and another showing an increase in SPL in response to hormone
therapy during puberty (5).

Testosterone Therapy
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Short-term use of intramuscular administration of testosterone esters has been reported often (90–
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94) (Table 3). Adverse effects have rarely been described, and may include a temporary acceleration
in growth rate with a transient advance in bone age maturation, but any effect on final height has
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not been reported (90). There are no standard guidelines or consensus on the dosage, method of
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administration or duration of T therapy in boys with micropenis. Since the 1970s, several studies
have reported a regimen of intramuscular depot-testosterone 25 mg, administered monthly, in one

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or two 3-month courses (90,92,94,95). This regimen of T enanthate 25 mg every 4 weeks, has been
reported to show an increase in penile length of over 100% in prepubertal boys with CHH (92),
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anorchia (93), isolated micropenis (95) and hypospadias with no demonstrable AR or SRD5A2
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variants (94). Arisaka et al. also documented a significant increase in SPL in 50 prepubertal boys
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treated with T cream 5% (10 mg/daily applied directly to the phallus) for a duration of 30 days. In
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this study, the boys had an age range between 5 months and 8 years and the increase in SPL was
noticed to be greater in those who were older. Transdermal T was also associated with a rise in
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plasma levels of testosterone and IGF-1 although there was no rise in plasma osteocalcin as a marker
of bone formation (96). There is a need to understand the optimal age of therapy for maximal effect
(97,98) as this may be related to the period when there is maximal androgen sensitivity perhaps
based on maximal tissue expression of AR (99). Given that tissue AR expression is high in early
infancy, it would seem appropriate to use androgens at that point but it remains unclear whether
such early use of androgens has any benefit on penile length in adulthood (100–102) (Table 3).
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Studies in rats with micropenis suggest that therapy at an early stage may be less effective in
promoting penile growth than at an age which would be equivalent to puberty (98). More recently,
testosterone therapy has also been described for the management of scrotal hypoplasia in young
children (103).

Topical Dihydrotestosterone gel treatment
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The effect of topical administration of dihydrotestosterone (DHT), the non-aromatizable form of
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testosterone, in undervirilized children with 5-reductase deficiency, was first described in 1990 by
Carpenter et al. (104). Since then, the use of DHT 2.5% gel has been reported in several studies, as
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an alternative to intramuscular T, especially in boys with PAIS or 5-reductase deficiency (104–111)
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(Table 4). Although high dose intramuscular T may promote the virilization of the external genitalia
in these conditions (112), there is a risk that aromatization of the high levels of circulating
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testosterone may lead to a premature growth spurt, precocious puberty, bone age advance and
pronounced gynaecomastia (113,114). On the other hand, the supply of DHT gel has often been
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erratic and there is also a risk of cross-contamination of close contacts (especially children and
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women) if patients do not follow application instructions (115). As for T therapy, there are no
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standardized guidelines or consensus on therapeutic regimen for DHT transdermal gel application to
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genital skin. The majority of studies that have reported a clear effect on SPL have used a daily dose
of 12.5 mg in boys <10 yrs of age and 25 mg in boys 10 yrs of age, for 4-16 weeks (105,109).
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Charmandari et al. documented a significant increase in SPL at a lower dose of 0.2-0.3 mg/kg/daily,
for 3-4 months (106). Adverse effects that have been documented include a transient decrease of
high-density lipoprotein-cholesterol: total cholesterol ratio and increase of alkaline phosphatase
(105); patients may also experience a rash and an itch of the genital skin (105). A more detailed
investigation of other wider effects of DHT such as that on haematocrit have not been investigated.
The clinical response in SPL to DHT treatment can be variable, depending on the underlying
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diagnosis and the age of therapy; in those with PAIS, response to DHT may vary according to the
specific AR variant (107,116). In clinical practice, an increase in SPL has been reported in PAIS (107)
and 5-reductase deficiency (109) in pre and peri pubertal patients but not in adults. However, the
response in cases of 5-reductase deficiency has not been as marked as expected (109). It has been
proposed that DHT may play an important role on AR expression, promoting synthesis and

repressing degradation (109,117); for this reason, intracellular DHT deficiency could reduce
androgen sensitivity in DHT-dependent tissues (109,118), explaining the limited effect of exogenous
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DHT in 5-reductase deficiency.
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Gonadotropin treatment
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The first report of micropenis treatment with hCG dates back to 1993, when Almaguer et al.
described noteable penile growth in six neonates after three hCG intramuscularly injections (119).
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Subsequently, treatment with recombinant gonadotropins was proposed as an alternative treatment
to T in male infants and peripubertal boys with CHH, as a treatment that would mimic the
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physiological activation of hypothalamic-pituitary gonadal axis (120). In 2002, Main et al. first
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reported treatment with recombinant gonadotropins in an infant diagnosed with CHH (121).
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Therapy consisted of recombinant LH (20-40 IU) and FSH (21.3 IU) twice weekly for approximately 7
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months and was successful in improving penile length, while inducing testicular growth and
mimicking physiological minupuberty (121). Further studies have reported the effectiveness of
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gonadotropin treatment in increasing SPL in boys with CHH during the first year of life (120,122–
124). Bougneres et al. described the continuous infusion of gonadotropins with an insulin pump in
two neonates with micropenis and CHH (123). Patient 1 began continuous sc infusion at 8 wk (rhLH
56 IU and rhFSH 67 IU daily) until 25 wk of life; patient 2 started continuous sc infusion at 20 wk
(rhLH 50 IU and rhFSH 125 IU daily) until 48 wk of life. SPL increased from 8 to 30 mm in patient 1
and from 12 mm to 48 mm in patient 2, with a concomitant increase in testicular volume and serum
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testosterone, inhibin B and AMH in both neonates (123). However, in general, reports of
gonadotropin treatment during the neonatal and infant period are still limited. Given the respective
differences in the half-life of hCG and LH (121), there is a need for further comparison of the relative
efficacy of these two drugs. In addition, further long-term studies are required to explore outcomes
such as fertility (62) (Table 5).

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Surgical management of micropenis
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In 1996, Wessels et al. provided guidelines for penile elongation, suggesting that only men with a
flaccid length of less than 4 cm or a SPL of less than 7.5 cm should be considered for surgical
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treatment (125). Since the first reconstructive intervention, reported by Hinman in the early 1970s
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(126), several surgical techniques have been developed (127). However, the role of surgery in the
management of micropenis is limited, with multiple techniques described with little in the way of
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high-quality evidence to guide the clinician. Surgery is only performed in adulthood and is reserved
for the most extreme cases. The surgical options can be divided into techniques that lengthen the
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penis, options to augment the girth of the penis, surgery to make the penis appear larger and
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replacement of the phallus altogether. To increase penile length, the suspensory ligament can be
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released and this can be performed in conjunction with a V-Y dorsal incision (128–130). Other
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techniques, such as the sliding elongation (131,132) and penile disassembly (133) have been
described. The increase in penile length is small (1-3 cm) (127) and subsequent scarring can cause
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retraction and a reduction in length. There can also be problems with erectile function and stability
of the penis, which can affect sexual function. The girth of the penis can be increased by the
injection of substances around the shaft of the penis: hyaluronic acid, liquid silicone, polyacrylamide
and autologous fat have been tried, with limited success. The main issue has been reabsorption of
the substances injected or the precipitation of scarring, that affects function or causes retraction of
the penis (134–136). The perceived length of the penis can be increased with removal of suprapubic
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fat. This can be attempted with weight reduction measures, but can also be augmented with
removal of suprapubic fat, using liposuction or more radical surgery (137). The penis itself can also
be replaced with an augmentation phalloplasty and many techniques have been described so far
(138). Currently, a radial-artery-based forearm free flap is employed with reasonable cosmetic
outcomes and acceptable donor complications (139). However, despite the evolution of these

techniques, they cannot replicate the normal anatomy and function of the penis and clearly further
research is needed to identify the best surgical procedure, in terms of which intervention will
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provide the highest long-term patient satisfaction and the lowest likelihood of post-operative
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complications.
Psychosocial outcomes us
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Although men with micropenis may have normal experience of sexual pleasure and orgasm (140–
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142), sexual dissatisfaction has also been reported: having a micropenis has been reported to have a
negative impact on sexual self-confidence, leading to social or sexual avoidance (143–145). It is a

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matter of concern that, even after hormonal or surgical treatment in childhood and/or adolescent
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age, a different genital appearance may contribute to poor self-esteem, social anxiety and reduced
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quality of life (146,147). Whether or not a clear correlation exists between penile dimensions and
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sexual dysfunction and long-term quality of life remains unclear, as the majority of studies have not
used standardized and validated instruments (3). In addition, counseling of the parents of affected
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boys and active involvement of the partners of affected men may be associated with better
outcomes (3), in terms of achieving greater self and social acceptance of the condition. Thus,
psychological counseling and long-term psychological support should be provided with an age-
appropriate explanation of the diagnosis. The availability of psychological support is known to be
particularly low for adults with conditions affecting sex development (148) and those who do
provide this support should also have links to experts in sex therapy, in case this is required.
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Conclusion and future directions
In summary, micropenis needs a multidisciplinary approach for its assessment, management and
treatment so that an individualized plan can be made for each patient. There is a lack of systematic

studies comparing the impact of the wide range of hormone therapies that are available on long-
term outcomes, including quality of life and sexual satisfaction. To date, research has been
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hampered by a small sample size, heterogeneous diagnoses and assessment tools and there is a
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need for a greater collaborative effort in collecting standardized data so that all real-world or
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experimental interventions performed at an early age can be studied systematically into adulthood.
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Data availability statement: Data sharing is not applicable to this article as no datasets were
generated or analyzed during the current study.

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33
Figures and Tables
t
ip
Figure 1 (a-b) A schematic figure of the possible cross talk between androgen and Wnt/β-
catenin signaling for genital tubercle (GT) masculinization in mice. Activation of the
cr
Wnt/β-catenin signaling pathway is necessary for GT masculinization. Dkk2
signaling, is regulated negatively us

(Dickkopf-related protein 2), encoding an extracellular antagonist of Wnt/β-catenin
by androgens (Testosterone and

an
Dihydrotestosterone) through the androgen receptor (AR). (a) Dkk2 is highly
M
expressed in female GT mesenchyme. (b) In the male GT, Dkk2 is regulated
negatively by AR, permitting the activation of the Wnt/β-catenin signaling. See

d
Reference 9 for details. ARE (Androgen responsive element); DHT

e
(Dihydrotestosterone).
pt
(c-d) Epigenetic regulation of murine external genitalia masculinization. (c)

ce
Androgen-induced genes that are responsible for masculinization of the external
genitalia are regulated by androgen receptor (AR). (d) House-keeping transcription

Ac
factor genes, such as Specificity protein 1 (SP1) and Activator protein 1 (AP1) are
required as co-factors form modulating histone modifications to promote
masculinization. Hence such genes are necessary to regulate the competency of the
sexual differentiation of the GT. See Reference 10 and 11 for details.
Created with Biorender.com
34
Figure 2 SPL in boys across childhood and adolescence in different ethnic backgrounds. The
numbers refer to the bibliographic citation in References and Table 1.

t
ip
cr
us
an
M
e d
pt
ce
Ac
35
Table 1. Summary of studies reporting stretched penile length (SPL, expressed as median or mean
and SD) in full-term newborn (except for ref 44, male infant born at 30-36 weeks of gestation), from
a wide range of ethnic backgrounds.

t
Ref Year Country n SPL (cm) -2.5 SDS (cm)
ip
32 1942 USA 125 3.75 NA
57 1975 USA 37 3.5 ± 0.7 2.5
cr
33 1987 Japan 25 2.9 ± 0.5 1.4
43 1989 Indonesia 336 2.9 ± 0.2 2.4
44
45
1998
2001
Australia
Canada
188
105
us (0.16 x GW) -2.27
3.4 ± 0.3
NA
2.7
an
46 2002 Saudi Arabia 379 3.6 ± 0.57 2.2
47 2006 Europe 1962 3.5 ± 0.4 2.5
48 2006 Taiwan 156 2.9 ± 0.4 1.9
M
36 2007 Brazil 126 4.7 ± 0.8 2.7

49 2007 Mexico 781 2.7 ± 0.5 1.5
50 2009 Malaysia 195 3.5 ± 0.4 2.5
d
38 2010 Europe 310 3.6 ± 0.46 2.5

e
51 2014 Nigeria 226 3.4 ± 0.5 2.2

40 2014 Japan 1210 3.1 ± 0.26 2.5
pt
52 2016 India 1015 3.3 ± 0.38 2.4

41 2016 Korea 86 4.1 ± 0.8 2.1
ce
53 2017 Turkey 249 3.2 ± 0.55 1.8

34 2018 Egypt 37 3.5 ± 0.6 2.0
Ac
42 2018 China 98 2.8 ± 0.5 1.6

54 2018 Iran 203 2.6 ± 0.15 2.2
55 2019 Sri Lanka 369 3.0 ± 0.37 2.1
56 2020 Europe 174 3.1 ± 0.54 1.8
22 2021 USA 197 3.6 ± 0.5 2.4
36
Table 2. Conditions associated with micropenis
Hypogonadotropic hypogonadism

Isolated
Combined with other pituitary hormone deficiency (hypopituitarism)
Syndromic conditions:
 Prader-Willi syndrome
t
 Bardet-Biedl syndrome
ip
 Laurence-Moon syndrome
 Charge syndrome
cr
 Silver Russel syndrome
 Rud’s syndrome
Hypergonadotropic hypogonadism
Congenital anorchia
us
Klinefelter syndrome and other X chromosome aneuploidies
Disorders of gonadal development:
an
 Sex chromosome mosaicism
 Partial gonadal dysgenesis
Syndromic conditions, eg:
M
 Down syndrome
 Prader-Willi syndrome
 Bardet-Biedl syndrome
d
 Laurence-Moon syndrome
Disorders of androgen synthesis
e
3-beta-hydroxysteroid dehydrogenase deficiency

pt
17-beta-hydroxysteroid dehydrogenase deficiency

17,20-lyase deficiency isolated or combined with 17-alfa-hydroxylase deficiency
5-alfa-reductase deficiency
ce
Disorders of androgen action

Partial androgen insensitivity syndrome
Growth hormone deficiency
Ac
Penile agenesis (aphallia)

Maternal use of antifungals
Environmental endocrine disruptors
Non-specific 46 XY DSD or Idiopathic Micropenis (ie cases that do not have any evidence of
endocrine or genetic abnormalities)
37
Table 3. The effect of testosterone treatment on stretched penile length (SPL)
Age n Condition SPL before T treatment SPL (SDS)

treatment (SDS)
Guthrie et 4 T cypionate 25 mg 1.8-3.5 cm
al. 1973 34 mo Prader-Willi every 3 weeks for 3
12 mo Prader-Willi months
21 mo NS Syndrome
t
6 mo NS-DSD
ip
Velasquez 0.7 ± 1 mo 13 Micropenis -4.6 ± 1.0 4-8 injections of T 2.8 ± 0.7
cr
et al. 1998 7.6 ± 1.5 -2.5 ± 1.0 heptylate (100 1.5 ± 0.2
2
mo -3 ± 1.0 mg/m ) every 2 weeks 2.3 ± 1.0
4.5 ± 2.5 y
0.4 ± 0.5
mo
27 Hypospadias
us
-4.0 ± 2.0
-2.5 ± 0.0
-3.0 ± 0.0
1.9 ± 1.2
0.8 ± 0.8
0.5 ± 0.2
an
7.6 ± 5 mo
5 ± 3.5 y
Bin-Abbas 4 mo – 2 y 4 HH -4 T enanthate 25-50 mg 2.4

M
et al. 1999 every 4 weeks for 3-6

months
6 – 13 y 4 HH -3.4 2
d
Arisaka et 5 mo – 8 y 50 NS-DSD 18.9 ± 4.4 mm T cream 5% 10 mg 8.4 ± 0.7 mm

e
al. 2001 daily for 30 days

pt
Zenaty et 0.7 ± 0.5 y 19 Bilateral anorchia -2.8 ± 0.8 3-4 injections of T 1.9 ± 1.3
al. 2006 heptylate (50-150
2
mg/m ) every 2-4
ce
weeks
Ishii et al. 2.6 ± 1.8 y 19 Micropenis -3.0 ± 0.8 T enanthate 25 mg 1.4 ± 0.7
Ac
2010 every 4 weeks up to 3

1.4 ± 1.3 y 17 Hypospadias 0.8 ± 0.6 times 0.9 ± 0.6
HH: Hypogonadotropic Hypogonadism
NS-DSD: Non-specific DSD
NS Syndrome: Non-specific syndrome
T: Testosterone
38
Table 4. The effect of dihydrotestosterone treatment on stretched penile length (SPL)
t
ip
Age n Diagnosis SPL before DHT treatment SPL
cr
treatment
Carpenter et 9 mo 1 SRD5A2 def 1.8 cm 2% DHT cream, 25 2 cm
al. 1990 mg/daily, for 4 mo
Odame et al.
1992
6y 1 SRD5A2 def
us
2.5 cm 2.5% DHT gel, 2.5 gr
twice daily for 3 mo
2 cm
an
9 mo 1 SRD5A2 def 0.5 cm 2.5% DHT gel, 2.5 gr 2.1 cm
twice daily for 6 mo
M
Choi et al. 3 – 15 y 22 <2 SDS <10 y: 2.5% DHT gel First 4 weeks:
1993 13 NS-DSD 12.5 mg/daily for 8 +153 ± 17%
3 PAIS weeks
2 HH Second 4
d
2 DAS >10y: 2.5% DHT gel weeks:

e
2 GHD 25 mg/daily for 8 118 ± 13%

weeks
pt
Charmandari 6 <2.5 SDS 2.5% DHT gel, 0.15-

et al. 2001 8.3 y SRD5A2 def 0.33 mg/Kg/daily, 1.1 cm
ce
1.9 y Robinow syndrome for 2.5-4 mo 0.5 cm

3-0 y Buried micropenis (<3 y: 2.5 mg/daily) 2 cm
7.8 y Buried micropenis (>3 y: 5.0 mg/daily) 2 cm
2.0 y Micropenis, 1.5 cm
Ac
7.6 y hypospadias no response

Micropenis
Bertelloni et 3 SRD5A2 def 2.5% DHT gel, 2.5 gr
al. 2007 NA 1.5 cm twice daily for 3-6 1.6 cm
mo
NA 1.2 cm 1.8 cm
2 mo 1.6 cm 2.3 cm
Becker et al. 3 PAIS 2.5% DHT gel, 0.3

2015 24 y 6.1 cm mg/Kg/daily for 4 no response
13 y 3.5 cm mo 2.2 cm
11 y 2.5 cm 1 cm
39
Xu et al. 4.1 ± 3.4 23 1.68 ± 0.6 2.5% DHT gel, 0.1- After 3 mo, 22
2016 y 16 NS-DSD cm 0.3 mg/Kg/daily for pt:
5 SRD5A2 def 3-6 mo -0.11 ± 0.45 cm
2 PAIS
After 6 mo, 15
pt:
-0.22 ± 0.43 cm
Sasaki et al 4 SRD5A2 def 2.5% DHT gel, 12.5-

2019 11 y -1.9 25 mg/daily, for 8- 1.2 cm [1.5
10.5 y -3.1 16 weeks SDS]
8y -2.3 2.8 cm [3.4
4y -2.7 SDS]
1.4 cm [2.3
t
SDS]
ip
1.5 cm [2.2
SDS]
cr
DAS: Disorders of Androgen Synthesis
us
DHT: Dihydrotestosterone
GHD: Growth Hormone Deficiency

an
NA: Not available

M
NS: Non-specific
PAIS: Partial Androgen Insensitivity Syndrome

d
SRD5A2 def: 5α-reductase-2 deficiency

e
pt
ce
Ac
40
Table 5. The effect of gonadotropin treatment on stretched penile length (SPL)

Age n Diagnosis SPL before Treatment SPL
treatment
Almaguer Neonates 6 NS-DSD 8-20 mm hCG 1500 IU x 3 days 0.25-
t
et al. 1993 0.75 cm
ip
Main et al. 1 HH 16 mm
2002 7.9-9.6 mo rhLH 20 IU + rhFSH 21.3
cr
IU x2/week
us
9.6-11.3 mo rhLH 40 IU + rhFSH 21.3 8 mm
IU x2/week
12.2-13.7 mo rhFSH 21.3 IU x2/week + 11 mm

an
T suppositories 1 mg/day
Bougneres
et al. 2008 8 wk 1 Hypopituitarism 8 mm CSI: 56 IU rhLH+ 67 IU 13 mm
M
rhFSH/daily, for 17
weeks
20 wk 1 HH 12 mm
CSI: 50 IU rhLH+ 125 IU 36 mm
d
rhFSH/daily, for 28
weeks
e
Kim et al. 18.9 ± 2.2 y 20 HH 5.1 ± 1.9 hCG im 1500-2000 IU x 2 ± 1.7

pt
2011 3/week, for 8 weeks cm

ce
Stoupa et 1.5 mo 1 PAIS 13 mm CSI: 75-225 IU rhLH+ 75 25 mm

al. 2016 IU rhFSH/daily, for 3-6
5.5 mo 1 Hypopituitarism 15 mm mo 30 mm
Ac
4 HH
4.5 mo 6 mm 32 mm
4.5 mo 15 mm 20 mm
3.0 mo 20 mm 28 mm
3.5 mo 11 mm 34 mm
Kohva et
al. 2019 4.2 mo 1 Charge 14 mm rhFSH sc 7.5-16.7 IU x 2- 17 mm
syndrome 3/week, for 3-4.5 mo + T
4 enanthate 25 mg every 4
0.7 mo Hypopituitarism 10 mm weeks, for 3 mo 14 mm
3.1 mo 15 mm 9 mm
1.3 mo 24 mm 11 mm
41
3.3 mo 23 mm 7 mm
CSI: Continuous subcutaneous infusion
hCG: Human chorionic gonadotropin

NS: Non-specific
PAIS: Partial Androgen Insensitivity Syndrome
t
ip
rhFSH: Recombinant human FSH
rhLH: Recombinant human LH
cr
T: Testosterone
us
an
M
e d
pt
ce
Ac
42
43
t
ip
cr
us
an
Figure 1
M
d e
pt
ce
Ac
44
t
ip
cr
us
an
Figure 2
M
d e
pt
ce
Ac

Congenital Micropenis Etiology and Management

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Congenital Micropenis: Aetiology And Management

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Professor S. Faisal Ahmed, MD FRCPCH,

Developmental Endocrinology Research Group,

School of Medicine, Dentistry & Nursing, University of Glasgow,

Office Block, Royal Hospital for Children,

1345 Govan Road,

Glasgow G51 4TF, UK

Disclosure statement: Authors have nothing to declare.

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systematically into adulthood.

Keywords: Micropenis, testosterone, gonadotropins, DSD.

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micropenis is relatively arbitrary. However, the identification of a micropenis is important as it may

It is expected that a clearer understanding of penile development, normal variations, the

pathophysiology of micropenis as well as standardized long-term follow-up will improve this

Development of the penis

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(Dickkopf-related protein 2), that encodes an extracellular antagonist of canonical Wnt/β-catenin

corresponds to the increased production of testosterone by fetal testis, documented as 150-400

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played by determinants of skeletal and genital development.

Environment & Epidemiology

The detrimental effect of environmental prenatal exposure to endocrine disruptors on the

maternal use of antifungals (25,26), as well as a reported association between exposure to

exposure to endocrine disruptors when assessed by measurement of antenatal urinary

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(0.16 x weeks of gestation) -2.27 (44).

not been regularly measured when assessment is undertaken for micropenis.

features of a congenital syndrome with multisystem abnormalities (59). Endocrine causes of

micropenis can be attributed to a defect of the hypothalamic-pituitary-gonadal axis (congenital

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micropenis is instinctively considered to be an exclusively male condition, it is important to bear in

isolated or combined with other urogenital anomalies (hypospadias, undescended testes,

diagnosis may be really challenging. The coexistence of neonatal metabolic or neurological

anomalies (such as neonatal hypoglycemia, prolonged jaundice, hypotonia) and/or dysmorphic

features needs to be considered to exclude concomitant absent production of other anterior

pituitary hormones (congenital hypopituitarism) and/or syndromic diseases, mentioned above. In

hypogonadotropic hypogonadism (CHH) is suspected, measurement of LH, FSH and testosterone in

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additional clinical utility of INSL3 as a biochemical marker of hypogonadotropic hypogonadism

requires further exploration (82).

suspected hypogonadotropic hypogonadism (84,85). Increasingly, diagnostic genetics utilize high

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may be normal in genetically confirmed cases of congenital hypogonadotropic hypogonadism (87).

Hormonal Management Of Micropenis

therapy during puberty (5).

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have reported a regimen of intramuscular depot-testosterone 25 mg, administered monthly, in one

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high-density lipoprotein-cholesterol: total cholesterol ratio and increase of alkaline phosphatase

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Subsequently, treatment with recombinant gonadotropins was proposed as an alternative treatment

56 IU and rhFSH 67 IU daily) until 25 wk of life; patient 2 started continuous sc infusion at 20 wk

such as fertility (62) (Table 5).

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negative impact on sexual self-confidence, leading to social or sexual avoidance (143–145). It is a