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Introduction

  1. Top of page
  2. Introduction
  3. The development of the Müllerian duct and prostate in the embryo
  4. BPH and leiomyoma
  5. The Müllerian duct remnants
  6. Hypothesis
  7. Acknowledgements
  8. References

After years of intensive research, several theories about the aetiology and pathogenesis of BPH have been proposed, including the DHT hypothesis, the embryonic reawakening theory and the stem cell theory [1,2]. Indeed, some of these mechanisms may act in concert with each other [2]. It is widely considered that BPH occurs exclusively in the transition zone of the adult prostate [3] and is a stromal disease [4,5]. Research shows that oestrogen receptors are located mainly in the stroma of the transition zone of BPH [6,7], and this is also the main site of accumulation of oestrogens [6,8]. In addition, oestrogenic stimulation can cause significant growth of the stroma [9,10]. The use of aromatase inhibitors can significantly reduce the size of BPH, particularly the stromal component [11,12]. Therefore, oestrogens are thought to play an inductive role in the occurrence of BPH [10]; the stroma of the transition zone is sensitive to oestrogens.

>However, this concept contradicts the traditional idea that the prostate originates from two parts, the Wolffian ducts and the urogenital sinus [13]. Both the peripheral and transition zone are thought to be derived from the urogenital sinus [13] and should thus be sensitive to androgens. However, there are many differences between them. First, their development is not synchronized; the transition zone develops significantly later than the peripheral zone [14]. Second, the diseases occurring in them differ, with BPH originating exclusively in the transition zone [3]. Third, in contrast to the peripheral zone stroma, the transition zone stroma is sensitive to oestrogens. Based on these different characteristics, I propose that the transition zone stroma may be derived from Müllerian duct mesenchyme (MDM). This review examines the relationship between the Müllerian duct and transition zone, to support this hypothesis.

The development of the Müllerian duct and prostate in the embryo

  1. Top of page
  2. Introduction
  3. The development of the Müllerian duct and prostate in the embryo
  4. BPH and leiomyoma
  5. The Müllerian duct remnants
  6. Hypothesis
  7. Acknowledgements
  8. References

During ontogenesis there is an intimate relationship between the Müllerian duct and prostate. First, the regression time of the Müllerian duct and development time of the prostate overlap. The Müllerian ducts develop during the sixth week of gestation in the human. In the female they fuse to form the female reproductive tract anlagen. However, in the male the Müllerian duct degenerates by 8 weeks of gestation because of inhibition by Müllerian-inhibiting substance (MIS), which is produced by the fetal testis. By 16 weeks the caudal end of the duct regresses to the level of the ejaculatory ducts. Simultaneously, the urogenital sinus epithelium starts to bud from the 10th week, under the influence of androgenic hormones from the fetal testis [15]. Numerous epithelial outpouchings from the urethra develop, and penetrate surrounding mesenchyme to form the prostate primordia.

Second, the Müllerian duct and prostate are linked spatially. The Müllerian ducts initially run parallel and lateral to the mesonephric ducts, and then cross ventral to the mesonephric duct to meet the contralateral Müllerian duct and fuse in the midline. The caudal end adjoins the posterior wall of the urogenital sinus immediately between the orifices of the Wolffian ducts. The meeting point is named ‘Müller’s tubercle' because of a transient swelling; it expends distally to form the verumontanum. The prostate originates from the urogenital sinus epithelium between the bladder and membranes portion of the urethra [15]. In adulthood, the site and course of the transition zone are approximately consistent with those of the Müllerian duct in the embryo; it is located on top of the verumontanum, posterior and bilateral to the urethra, and ventral to the ejaculatory ducts (or the Wolffian ducts).

Animal experiments have shown that MIS induces the regression of the Müllerian duct, triggering cell death by altering mesenchymal-epithelial interaction. The site on which MIS acts directly is the mesenchymal cell layer surrounding the duct, whereas apoptotic cells are located at the epithelium [16]. The outer diameter of the duct does not change [17]. These data indicate that the regression of the Müllerian duct is only of the epithelium, whereas its mesenchyme persists. This is the case in the human male, which is shown by the presence of Müllerian duct remnants, including the verumontanum and prostatic utricle in the adult prostate [15]. This, together with the intimate relationship in time and space between the regression of the Müllerian duct and development of the prostate, prompts the speculation that the epithelial buds of the urogenital sinus most probably penetrate the caudal mesenchyme of the degenerating Müllerian duct to form part of the prostate.

Experiments in rats show that a small supplement of oestrogen to male fetuses can cause significant enlargement of the developing prostatic epithelial buds, utricle and seminal vesicles, with the cranial dorsolateral prostatic buds enlarging the most [18]. This result suggests that both the dorsolateral prostate and utricle may contain oestrogen-sensitive tissue of the same origin. This effect has not been shown in the human prostate, but the dorsolateral prostate in rats is believed to correspond to the region susceptible to BPH in men [18–20]. Therefore, I propose that the MDM does not disappear, but persists with the verumontanum and prostatic utricle, and is probably incorporated into other organs, such as the transition zone of the prostate.

BPH and leiomyoma

  1. Top of page
  2. Introduction
  3. The development of the Müllerian duct and prostate in the embryo
  4. BPH and leiomyoma
  5. The Müllerian duct remnants
  6. Hypothesis
  7. Acknowledgements
  8. References

There are two similarities between BPH in men and leiomyoma in women. First, leiomyoma is caused by persistent stimulation from oestrogens and progesterones [21]; similarly, oestrogens are thought to be an important factor in the aetiology of BPH. Furthermore, persistent stimulation by oestrogens alone can cause prostatic hyperplasia. Both Goodwin and Cummings [22] and Brown and Wilson [23], respectively, reported a male-to-female transsexual presenting with BPH arising from the long-term use of oestrogens after bilateral orchidectomy. These two cases were characterized by stromal hyperplasia, and the same phenomenon has been reported in animal experiments. Habenicht and el-Etreby [24] found that in the prostate of castrated adult male monkeys treated with 17 β-oestradiol for 3 months, the periurethral zone developed stromal hyperplasia. This development was particularly evident and predominantly in the dorsolateral region.

Second, both BPH and leiomyoma are characterized by variably sized nodules. Histologically, BPH nodules are classified into five types: stromal, fibromuscular, muscular, fibroadenomatous, and fibromyoadenomatous. The most common nodules are of the last type, which contains all elements including glandular tissue, various fibrous connective tissue, and smooth muscle cells. Some investigators consider that the glandular elements of this nodule originate from the glandular ducts in its vicinity, by stromal inductive effects [3,25]. Thus BPH results virtually from stromal hyperplasia, which stimulates growth of the glandular component. The common histological pattern of leiomyoma is also composed of smooth muscle with a variable fibrous-tissue component; this is similar to that of the fibromuscular nodule of BPH [25].

The Müllerian duct remnants

  1. Top of page
  2. Introduction
  3. The development of the Müllerian duct and prostate in the embryo
  4. BPH and leiomyoma
  5. The Müllerian duct remnants
  6. Hypothesis
  7. Acknowledgements
  8. References

In men, some remnants of the Müllerian duct persist in the adult prostate, including the prostatic utricle, verumontanum and appendix of the epididymis. The verumontanum and transition zone are able to hypertrophy at the same time, under stimulation by oestrogens [22]. Gagucas et al.[26] first described verumontanum mucosal gland hyperplasia (VMGH), which occurred exclusively in the verumontanum and adjacent posterior urethra where the ejaculatory ducts and utricle emptied into the urethra. This proliferative epithelium showed immunohistochemically strong positivity for PSA and was thus homologous to urothelium and prostatic acini; the cases were 47–87 years old. Gaudin et al.[27] also reported the presence of this disease in patients aged 57–70 years.

From these descriptions there are several similarities between BPH and VMGH. First, the ages of occurrence are identical. Second, the vermontanum ‘stroma’, a remnant of the Müllerian duct, is sensitive to oestrogens, a characteristic shared with transition zone stroma. Furthermore, the vermont anum can hypertrophy with the prostate under the stimulation of oestrogens alone. Third, their hyperplastic epithelial cells are all derived from the urogenital sinus. These data suggest that the verumontanum and transition zone share the same origin, and thus both VMGH and BPH are hyperplasia of the Müllerian duct remnants.

Hypothesis

  1. Top of page
  2. Introduction
  3. The development of the Müllerian duct and prostate in the embryo
  4. BPH and leiomyoma
  5. The Müllerian duct remnants
  6. Hypothesis
  7. Acknowledgements
  8. References

Genesis of the transition zone

These relationships between the transition zone of the adult prostate and Müllerian duct suggest that the transition zone may be derived from two parts, i.e. the urogenital sinus epithelium and MDM. In the male fetus, MIS inhibits the mesenchyme of the Müllerian duct to thereby elicit its epithelial regression. During the same period, some urogenital sinus buds penetrate this mesenchyme and substitute its regressing epithelium. After this, the urogenital sinus epithelium and MDM incorporate, to develop into the transition zone of the prostate under stromal-epithelial interactions. The mesenchyme does not disappear, but persists.

Development of the transition zone

The development of the transition zone has a significantly different pattern from that of other regions of the prostate, because of the influence of sex hormones. In the fetus, animal experiments have shown that testosterone produced by the fetal testis enhanced the inhibitive effects of MIS on the Müllerian duct [28], and antagonized the inductive effects of oestradiol on both gonads and the duct [29]. Therefore, the differentiation and development of the transition zone can be inhibited despite the existence of the strong maternal oestrogenic environment. After birth, great changes take place in the serum levels of sex hormones in the human male neonate. During the first 6 months of life serum testosterone levels rise as high as the lowest limit of a normal adult, which is 60 times higher than normal male prepubertal testosterone levels. Progesterones also have a transient surge at about 2 months of age. However, the serum oestradiol levels that are very high at birth fall rapidly to very low levels in the first few days afterward. The same phenomenon also occurs in the early life of rats [30]. Experiments in rats showed that the neonatal androgen surge permanently imprinted the ventral prostate, and determined its subsequent responsiveness to androgens and growth in adulthood [31,32], but this effect was inhibited by neonatal oestrogenic exposure [31,33]. Although the imprinting effects on the prostate have not been determined for the human prostate, the same surges of sex hormones may play the same role as those in the male rat [30]. Thus it is possible that the androgen surge characterized by long-term high levels may result in complete differentiation in the peripheral zone tissue. In contrast, persistent inhibition of MIS [34] and rapid decrease of oestrogens stunt the development of the MDM in the transition zone. Hence, the MDM cannot differentiate completely and remains in the embryonic state. The growth of glandular epithelium in this region is simultaneously retarded because of the lack of the induction by the stroma, although it is sensitive to androgens. Research has shown that high levels of serum MIS in human males are maintained until puberty, and then fall to baseline levels [35]. Thus in the prepubertal period, the morphogenesis of the transition zone appears to lag behind that of the rest of the prostate [14].

Because MIS declines after puberty, the development of the transition zone depends on oestrogens that are converted from testosterone by tissue aromatase. In human hyperplastic prostate tissue, aromatase is located mainly in the stroma [36,37] and is overexpressed [37]. However, the prevalence of histological BPH does not increase rapidly until men are ≈ 40 years old [38]. McNeal [14] has noted that repression of further growth potential appears to be less in the adult prostate than in the postpubertal prostate, as evidenced by the gradually increasing mass of the transition zone with age. I suggest that an explanation for this phenomenon is that aromatase is activated late in men; the maturation of aromatase activity in men does not normally become appreciable until late puberty [39–41]. Moreover, it may be influenced by various factors; research on genital skin has shown that DHT can stimulate aromatase activity [42], but testosterone reduces its activity [43]. From such data, I infer that under the long-term interactions of various factors, probably including the stimulation of DHT and inhibition of testosterone, aromatase activity in the transition zone stroma may be gradually enhanced, resulting in the local accumulation of oestrogens [44] and an increase in the oestrogen/testosterone ratio. When this hormonal milieu approaches given levels, the mesenchymal cells that are still in the embryonic state are reawakened and begin re-growth. In the course of growth of the transition zone, oestrogens and androgens are both required. Oestrogens play a critical role in causing the mesenchyme to develop, and the activated mesenchymal cells then stimulate the epithelial development through the stromal-epithelial interactions. This in turn promotes the development and maturation of the MDM. DHT acts indirectly to cause epithelial growth through the regulation of growth factors produced by the stromal cells [45].

Recently, research on early-onset significant BPH has revealed two features. First, this disorder is an autosomally dominant hereditary disease [46]; second, hereditary BPH is predisposed to an increase in stromal elements because the prostate, histologically, is characterized by a higher stromal/epithelial ratio than that of similar-sized prostates in older men with sporadic BPH [47]. I propose that this disease may result from an unusual increase in aromatase activity. Aromatase activity is also regulated by genetic factors; an autosomal dominant mutation that increases aromatase activity occurs in both animals [48] and human [49]. The increased aromatase activity enhances the synthesis of oestrogens. Early elevated oestrogens can cause the transition zone stroma to develop and mature early, thus contributing to the increase in the ratio of stroma to epithelium.

Aetiology of BPH

Thus the aetiology of BPH should be interpreted monophyletically as a reactivation of the persistent MDM in the transition zone. This theory is also supported by Bierhoff et al.[50,51], who reported that the development of stromal nodules in BPH repeated the fetal sequence; this results from the reactivation of the MDM cells that have been in the embryonic state. This theory is therefore in agreement with the embryonic reawakening theory. Some investigators consider that BPH might be a stem-cell disease, resulting from abnormal maturation and regulation of the cell-renewal process [52]. These stem cells are exactly those MDM cells that have preserved the capacity for differentiation. They do not differentiate and develop until the hormonal milieu is suitable.

Generally, the development of BPH involves three processes: early diffuse gland growth, small nodule occurrence and later nodule enlargement [3]. The occurrence of the first diffuse growth is because in the transitional zone the MDM that has been stunted in the embryonic state recovers its development. The inhibition of aromatase activity may decrease further because free testosterone declines with age [53], which leads to the accumulation of oestrogens and a progressive imbalance of sex hormones in the transition zone. McNeal [14] noted that the number of large nodules increased significantly as men entered their seventh decade. This phenomenon is in agreement with the increases in oestrogen levels and ratio of oestrogen to androgen with age in BPH stroma [54]. Therefore, I propose that persistent oestrogenic stimulation results in the development of stromal nodules, the mechanism of which may be similar to that of female leiomyoma. If the surrounding duct epithelium penetrates the nodule with induction of the stroma, the nodule becomes larger under the stromal-epithelial interactions.

After comparing much data about the transition zone and Müllerian duct, I conclude that the transition zone epithelium originates from the urogenital sinus, and its stroma from the MDM. Although in male fetuses the Müllerian duct is inhibited by MIS, its mesenchyme persists and participates in the formation of other organs. During prostatic morphogenesis, the prostatic buds arising from the urogenital sinus penetrate the surrounding MDM, and are then incorporated to develop into the primordium of the transition zone. After birth, because of persistent inhibition by MIS and a rapid reduction of serum oestrogens, the development of the MDM is stunted in the embryonic state until adulthood. In adults, the MDM gradually recovers development because tissue oestrogens slowly increase. Therefore, aromatase activity that converts testosterone to oestrogens may determine the occurrence of BPH. There are various factors that may influence aromatase activity, e.g. stimulation of DHT, inhibition of testosterone and genetic factors. Their interactions result in the variable age of onset of BPH. The early diffuse growth of the transition zone may represent the recovery of development of the MDM. However, the genesis of nodules may result from persistent oestrogenic stimulation because antagonism on aromatase activity reduces with ageing, leading to the accumulation of oestrogens and progressive imbalance of sex hormones in the tissue; the mechanism may be similar to that of female leiomyoma.

References

  1. Top of page
  2. Introduction
  3. The development of the Müllerian duct and prostate in the embryo
  4. BPH and leiomyoma
  5. The Müllerian duct remnants
  6. Hypothesis
  7. Acknowledgements
  8. References