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Introduction

One of the most commonly encountered problems in the practice of sexual medicine has been the serious concern men frequently have about penis size starting from puberty to adulthood. Men are extremely anxious about their penile length [1]. The penis is credited with the dual function of coitus and micturition. In biology, the ability to transfer sperms denotes maleness of an organism. To a man, no matter what his socioeconomic status is, the size of the penis always matters [2].

Online content, visuals, peer pressure, and the belief that a bigger penis leads to better sexual satisfaction for the partner are lingering concerns that do not go away. Most of these men however, taken into consideration the great variation in size, turn out to be anatomically normal [3]. Across all cultures, the penis symbolizes masculinity, strength, and courage. History is abound with stories of men who have tried in desperation various techniques to increase penis size. It is said that the sadhus from India used weights suspended from the penis to stretch it much like a penile expander. These penises were not usable. They were simply stretched for the sake of size [4]. Some went to the extent of encouraging poisonous snakes to bite their penis like the Topinama of Brazil. Repeated bites would cause the penis to enlarge to a monstrous size [4].

The diagnosis of micropenis in clinical medicine is often a case of oversight. Micropenis is significantly different from small penis which is not clinically a true micropenis [3]. When misdiagnosed it can cause considerable anxiety to the patient and the parents. It can lead to unnecessary examinations and tests. The term micropenis should not be confused or included under broader headings like small penis or inconspicuous penis. A diagnosis of micropenis is made by measuring stretched penile length. This concept was first introduced by Schonfeld and Beebe in 1942 [5, 6]. Based on this, the definition of micropenis was accepted as a stretched penile length 2.5 standard deviations less than the mean for age group without the presence of any other penile anomalies [5, 6]. It can occur on its own or as a part of a syndrome. In the United States, the reported incidence was 1.5 in 10,000 male births between the years 1997 and 2000 [7].

Pathophysiology of Micropenis

Growth of the penis is controlled by androgenic hormones. The gonadal ridge differentiates into testis during embryonic development and placental human chorionic gonadotrophin (HCG) production drives secretion of testosterone in the Leydig cells of the testis. Dihydrotestosterone that is derived from testosterone drives penile differentiation that is completed by the 12th week of intrauterine life [8]. A significant increase in penile size occurs between the 2nd and 3rd trimesters of intrauterine life due to elevated levels of androgens that are seen between the 8th and 24th weeks [9].

There is an increase of penile length of approximately 20 mm from weeks 16 to 38 [8]. Thus we can understand that a true micropenis could be one that results from abnormal or an imbalance in the hormonal milieu that occurs after 12 weeks of gestation [10, 11]. So, either there is an inadequate production of androgens for stimulation of penile growth or an inadequate response of the penis to stimulation.

Etiology

The etiology of micropenis can be classified into the following three broad categories.

Hypogonadotropic hypogonadism: This is also known as pituitary hypothalamic failure. Here the hormones from the hypothalamus and pituitary are not adequate for stimulation of the gonads. Conditions such as Kallmann syndrome and Prader-Willis syndrome are part of this entity and micropenis is associated with it [11].

Hypergonadotropic hypogonadism: This is a condition where there is a failure of the gonads also known as primary testicular failure. The condition may be associated with syndromes like Robinow syndrome and Poly-X syndromes like Klinefelter syndrome, gene translocations, and trisomies of chromosomes 8, 13, and 18 [11].

Idiopathic: For reasons unknown, here the hypothalamus-pituitary-testicular axis is essentially normal. Irrespective of the etiology the question that should run foremost in the physician’s mind is whether the penis will respond sufficiently to hormonal stimulation for the infant to continue being raised as a boy or should gender reassignment be considered for him [12]. Table 10.1 summarizes all the possible causes of Micropenis.

Table 10.1 A brief overview of the various causes of micropenis
Full size table

Diagnostic Criteria

The key to treating a true micropenis lies in its early diagnosis as it allows for the different treatment modalities to be applied early. For an individual to be considered as having a micropenis, the phenotype should be male with a XY karyotype.

A small penis, foreskin, median raphe, and a normal location of the urethral meatus are required [13]. The length of the penile shaft along with the state of erection or nonerect can make the appearance of the micropenis to be either retracted or flaccid. Presence or absence of the corpora also aids in the appearance. The scrotal development may be one of underdevelopment or normal [14]. Usually the testicles are located in the scrotum, but testicular function is not guaranteed especially with certain syndromes. Volume may be below normal. Sometimes as part of a syndrome the normal descent of the testis may be affected. Features of feminization are usually absent.

How to measure penile length: Measurement of penile length is of utmost importance in a patient with suspected micropenis. If the stretched penile length of the penis is less than 2.5 SD (standard deviation of the mean) for the individual’s age a diagnosis of micropenis is made [15]. Also a 46XY karyotype with normal internal and external genitalia supports the diagnosis. Penile length should be strictly measured in a fully stretched penis and not in a flaccid one. A scale or a ruler traditionally is used to measure length [11]. To begin with the suprapubic fat pad should be compressed and if there is a foreskin it should be retracted. The glans is then held between the thumb and forefinger and the penis is stretched. The penis length is then estimated in the dorsal aspect from the tip of the glans till the pubic rami. An alternative method for estimating penis size will be with the help of syringe, where the needle end is cut and the piston is introduced in the opposite end (needle side). The flange aspect is then introduced over the penis that has to be measured; mild and gentle suction will then cause the penis to move up the syringe while simultaneously pressing down on the pubic fact gently. The penis size is then read by scale on the side of the syringe [15].

Differential Diagnosis

A number of conditions can mimic the diagnosis of a micropenis and it is of utmost importance that these conditions be diagnosed correctly so that there is no confusion. A web of skin under the penis, scar tissue which shrinks the penis by contracture, excess fat, insufficient or imperfect penile skin, and loose penile skin need to be differentiated from the diagnosis of a micropenis [16].

A buried penis occurs in obese children who are prepubertal. Here the main culprit is the suprapubic fat pad which covers and buries the penis [17]. Careful physical examination and correct measurement of penile length is key. The exact penile length can be estimated by applying gentle pressure on the fat tissue. A condition known as trapped penis results from fat pads in the suprapubic region that results from a lack of skin that should be available to cover the shaft [18]. This usually results following a circumcision or a trauma to the penis resulting in scarred prepubic skin. In this condition there is adhesion between the scrotal skin and the skin of the penis. Webbed penis is another differential diagnosis characterized by the penis that attaches by a skin tissue to the front of the scrotum [16]. Penile curvatures and penile agenesis are other conditions which need due consideration before confirming a diagnosis of micropenis [16, 17].

Investigating a Micropenis

Considering the many differential diagnoses, the diagnosis of micropenis can be quite challenging.

Laboratory investigation: A thorough endocrinology assessment helps determine the level of defect in the hypothalamic-pituitary axis. A concomitant evaluation of testicular function and central endocrine activity should be ideally done at the same time [19]. Serum estimates of FSH, LH, and total testosterone are usually adequate to assess adult testicular function. Elevated FSH and LH to twice the upper limit of normal reference range indicates hypergonadotropic hypogonadism, while extremely low FSH and LH and low testosterone indicates hypogonadotropic hypogonadism. In patients where bilateral undescended testis or anorchia is suspected, a HCG challenge test is done. A HCG challenge involves measuring testosterone response before and after administration of HCG. In this test, for children between 6 months and 14 years a dose of 1000–1500 i.m. can be given on an alternate day up to seven doses. The testosterone value is assessed before and after about 48 h of the last dose. Testosterone values rising beyond 200 ng/dL after a HCG test indicate the presence of a functional testis tissue [20, 21]. Determination of inhibin B and AMH levels, both which are produced by sertoli cells in the testis, gives us an idea of functioning testis tissue [21, 22]. A persistent mullerian duct syndrome is indicated by normal levels of inhibin B and low AMH [21, 22].

Imaging studies: Modalities such as ultrasound and MRI can be used for imaging. MRI imaging should be done for all children born with micropenis. MRI imaging helps assess the hypothalamus and pituitary. In children with craniofacial abnormalities assessment of the optic chiasm, corpus callosum, and fourth ventricle is done. In addition transverse brain images will best show the size of the olfactory sulci, which can be used to assess Kallmann syndrome as it is associated with anosmia [21].

Genetic testing: Genetic testing may be necessary to rule out syndromes that contribute to micropenis. Karyotype assessment using chromosomal analysis can be done for sex determination. Y fluorescence also helps in this matter [19].

Treatment

Goals of treatment: Goals of treating a man with micropenis should be realistic. The three key treatment objectives are (1) to provide the patient with a body image that will not lead to any embarrassment, (2) to engage in normal sexual intercourse, and (3) to help the patient achieve urination while standing normally. Achieving and/or reaching the target penile length for age is not a therapeutic goal.

An important aspect to keep in mind before we embark on treatment of micropenis is to understand what men and their female partners think about penis size as this may help dictate/decide management. An Internet survey of 52,000 heterosexual men and women was done to determine whether men with bigger penises had a more favorable body image compared to men who did not [2]. The study conducted by Lever et al. had one limitation in that it was based completely on patient’s perspective of penis size and other physical attributes. The study revealed that men who considered themselves to have a large penis had a more positive image of their body and considered themselves more attractive than those men who did not. Women were found to be more satisfied with their partners’ penis size than men with their own (84% vs. 55%). Studies in most cases have also found that most men complaining of a small penis in fact have a normal-sized penis [22].

Role of testosterone: The role of androgens is crucial in infancy for sex selection [23]. A trial administration of testosterone is done to assess the response either by intramuscular route or topical application. For a start 25 mg of either testosterone enanthate or cypionate is administered i.m. once in every 21 days for a 3-month period. Temporary rise of growth rate and a bone age advancement may be seen [24]. Guthrie et al. administered testosterone depot every 3 weeks for 3 months [24]. Main et al. suggested testosterone suppositories in boys with hypogonadotropic hypogonadism and noticed increase in penile length [25]. There has been no consensus method, duration, and dose of testosterone therapy for micropenis [20]. Moreover, it is a fact that none of these authors observed changes in testicular volume and AMH levels [26]. A good response is to expect a 100% increase in the penile length, although there is no global consensus on this. Sultan et al. consider a size increase of 3.5 cm to be adequate response to treatment. Some authors concur on repeating the applications within a short period [27].

Topical testosterone can be applied in infancy. Five percent testosterone cream was applied by Arisaka et al. in 50 infants and in children between the ages of 5 months and 8 years for 30 days [28]. Long-term dermal application of testosterone is found to promote skeletal as well as penile growth. Testosterone has positive effects on the growth of the penis during infancy. However, whether this growth continues into adolescence and even adulthood is not known [29]. During early adulthood a decrease in the number of androgen receptors is seen; thus application of testosterone early during development allows an upregulation of receptors. Hence treatment with testosterone before early adulthood is recommended [27].

Topical 5-alpha dihydrotestosterone (DHT) gel: Androgen insensitivity in prepubertal patients may benefit with the application of DHT gel to the periscrotal region. A thrice-daily application over a 5-week period showed an increase in penile length and acceleration in genital development [30]. It also worked in infants with 5-alpha reductase deficiency according to a study done by Bertelloni et al. [31]. Side effects were similar to testosterone; however minor skin irritations were seen [31]. This line of treatment can be tried in testosterone-resistant patients.

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH): Recombinant LH and FSH have been tried during infancy and early childhood with varying success especially in patients diagnosed with hypogonadotropic hypogonadism. With the addition of testosterone to subcutaneous injections of 20 IU of LH and 21.3 IU of FSH for a 6-month time frame given twice a week, an increase in penile length from 1.6 to 2.4 cm was noted as well as a 170% increase in testicular volume [25, 32].

Surgical Management

When medical treatment fails to achieve desired penile length surgical options may be considered. Hinman reported as early as 1970s the first reconstructive surgery on the penis. Despite the evolution of various techniques for penile reconstruction, the radial artery forearm flap remains the most popular technique of all [33]. Implants have also been combined with reconstructive surgery with better cosmetic outcomes [34]. However, complications still remain high with surgery [35].

Conclusion

In conclusion, micropenis is a diagnosis which is to be made bearing in mind the right technique to correctly estimate and compare mean penile length. It can occur independently or as a part of a syndrome. Endocrinologic assessment is key in helping to establish the diagnosis. Early diagnosis and early treatment should be instituted for best results. Surgery is fraught with complications and should be carefully chosen and performed by the most experienced. Finally, evidence suggests that even with an untreated micropenis, majority of patients who grow up as male seem to have normal sexual function.