Micropenis

Etiology

In human beings, the chromosomal sex combination is determined at fertilization either as female (XX) or male (XY). Early in fetal life, the embryo has both mesonephric duct (male) and paramesonephric ducts (females). Based on the presence or absence of the SRY gene (located on the Y chromosome), regression or development of one of these ducts will continue during organogenesis. The SRY gene stimulates gonadal differentiation into testicular tissue. At this early stage of development, the testes secrete three hormones that are very important in the sexual male differentiation process:

• Anti-Mullerian hormone (AMH): Function to regress the development of the paramesonephric ducts
• Testosterone: Function to stimulate the development of the mesonephric duct into internal male structures (seminal vesicle, vas deference, and epididymis)
• Dihydrotestrone DHT: Stimulate the growth of male sexual characteristics (scrotal sac maturation, increased penile length and testicular size)

Under the influence of these three hormones, the male reproductive and genitourinary systems start to develop during the late third of the first trimester (8 to 12 weeks of gestation). The human chorionic gonadotropin (hCG) stimulates the Leydig cells to secrete testosterone. Further metabolism in utero converts testosterone to dihydrotestosterone. High levels of fetal androgens During the second-trimester further accelerate penile growth.[1] In the postnatal period, further development of the male sexual characteristics takes place under the influence of the hormones regulated by the hypothalamic-pituitary axis (gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)). The highest postnatal androgen levels occur between the first and third months of life.[2] Undervirilization signs and micropenis usually result from disturbance of any of these steps. Such distribution can occur in any of the following[3]: 

• Kallman syndrome (hypogonadotropic hypogonadism, osteoporosis, hearing impairment, and anosmia)
• Hypopituitarism (hypoglycemia, hypogonadotropic hypogonadism, and growth disturbances)
• Prader Willi syndrome (hypotonia, obesity, intellectual disabilities, undescended testes, micropenis, small hands and feet)
• Growth hormone deficiency
• Androgen receptor defect and/or resistance
• Anorchia (absence of testes)
• Klinefelter (XXY)(small testicles, infertility, gynecomastia, poor coordination, and reading difficulties)
• Trisomies of the chromosomes 8,13,18 and 21
• Noonan syndrome (hypertelorism, short neck, low set ears, skeletal malformation, bleeding disorders, and pulmonary valve stenosis)
• Gonadal dysgenesis
• 5 alpha-reductase deficiency
• Rare types of congenital adrenal hyperplasia (deficiency in steroidogenic acute regulatory protein (STAR), 3 beta-hydroxysteroid dehydrogenase (3β-HSD), 17 α-hydroxylase)

In some cases, the etiology remains unclear even after performing an extensive evaluation.

Epidemiology

Micropenis incidence in North America is about 1.5 per 10,000 male newborns.[4] Research shows a slight statistical difference in the mean penile length between the White race, 2.6 cm, east Indian 2.5, and Chinese 2.3 newborns.[5] Other studies proposed specific penile length standards for the Brazilian, Japanese, and Turkish infants and children.[6][7][8]

History and Physical

Clinical diagnosis of micropenis often occurs after a detailed history and physical examination. After making the diagnosis, further testing to identify associated abnormalities and possible etiologies are necessary.

Detailed maternal history is the first step in evaluation for micropenis. Consanguinity and family history of ambiguous genitalia make inherited conditions more likely on the differential. Inquiry about maternal medication use is important, as the use of anti-androgen medications (flutamide, testolactone, enzalutamide, and spironolactone) can interfere with the in-utero virilization.

Physical examination assessment is the most crucial part of micropenis evaluation. Underverlization associated with low blood pressure and tachycardia can indicate adrenal gland insufficiency related to rare forms of congenital adrenal hyperplasia (CAH). Penile length accurate measurement is critical during the physical examination. The penis shaft should be maximally stretched. The distance is measured from the pubic symphysis (after pressing the suprapubic fat) to the tip of the glans (with the foreskin retracted as much as possible) dorsally. The average of multiple measurements can enhance accuracy. 

Specific penile length less than two and a half standard deviations of the mean for the corresponding age confirm the diagnosis.[3] Suggested lower limits of penile lengths in centimeters according to age are (represented graphically in figure 1):

• Preterm infants born at 30 weeks of gestation; 1.5
• Preterm infants born at 34 weeks of gestation; 2
• Term infants; 2.5 
• One-year-old; 2.6
• Five years old; 3.5
• Ten years old; 3.8
• Adults; 9.3

Careful and thorough palpation of the gonads is another step in micropenis evaluation to narrow the differential diagnosis. The appearance and the maturity of the scrotal sac, the presence and the location of the urethral meatus, the curvature of the penile shaft, and any dysmorphic features require careful evaluation.

Evaluation

Following diagnosis by physical examination, work up to identify the etiology and to guide the treatment plan is necessary.

A standardized approach for micropenis evaluation consists of:

• Hormonal level measurement (testosterone, dihydrotestosterone (DHS), luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
• hCG stimulation test to evaluate gonadal function ( measure testosterone hormone before and after hCG administration) testosterone levels below 300 ng/dL is suggestive of gonadal dysfunction[9]
• Underverlization form of CAH evaluation to rule out the rare types associated with undervirilized male (progesterone, 17-OH progesterone, androstenedione, and 17-OH pregnenolone)
• Pelvic ultrasound to evaluate the gonads and internal genital structures.
• MRI brain to evaluate the pituitary gland

Treatment / Management

The goals of micropenis management include:

• Minimize social embarrassment associated with micropenis
• The ability to achieve normal sexual function,
• Normal urinary function in the standing position

Medical or surgical interventions have had trials performed with variable responses. The primary etiology, age of presentation, degree of atrophy, and desired outcome usually dictate the treatment approach. A reasonable treatment plan for micropenis is a trial of medical therapy first, then surgical intervention if the medical treatment does not result in the desired outcomes.

Medical Treatment 

• Testosterone is available as an intramuscular injection or topical gel. Intramuscular (IM) testosterone (25 mg) given every three weeks for three months is a traditional dosing regimen followed by a pediatric endocrinologist.[10] Arisaka et al. studied the use of 5% testosterone topical cream in children and infants' who are less than eight years of age. The outcomes were promising, as 45 out of 50 patients (90%) achieved a statistically significant increase in penile length and testosterone blood level after 30 days of treatment with topical testosterone.[11]
• Dihydrotestorne (DHT) (testosterone metabolite) reportedly has some efficacy (case reports and small case series), especially in infants with 5-α reeducate deficiency.[12][13]
• Human recombinant FSH and LH administration can be a consideration in children with hypogonadotropic hypogonadism.[14]
(B3)

Surgical Treatment

A penile reconstruction is an option if the response to medical treatment is inadequate. Surgical treatment usually achieves acceptable results. However, dissatisfaction with penile appearance is common among treated patients.  

Differential Diagnosis

The most crucial differential is to rule out is pseudo micropenis. In this condition, the penis appears small due to the surrounding tissue prominence or penile web that attaches the penis to the underlying skin. Meticulous thorough physical examination is essential to rule out pseudo-micropenis and avoid an invasive diagnostic evaluation and the associated patients' and their family's psychosocial stress. Chordee of the penis is another surgical condition that results in an abnormally curved penile shaft that can underestimate the penile length.