There is evidence that the inner myometrium develops earlier in utero and is visible before week 21 of gestation compared to the outer myometrium which only appears after 24 weeks of gestation [13]. In contrast to the well-defined circular and longitudinal layers found in rodents (Fig. 4.1) and in many other species, the microanatomy of the human uterus is complex. Confusion arises from the observation that the subserosal myometrium appears to be different to the inner myometrium. The outer myometrium contains large blood vessels with their own smooth muscle cell coat and sensory neurones that are under hormonal influence. The question arises as to whether there are distinct functions for the inner and outer myometrial layers and how the two layers are differentially regulated or affected by the presence of commonly encountered diseases such as adenomyosis and fibroids. The inner myometrium close to the endometrial junction exhibits higher cellular density compared to the outer myometrium and also higher nuclear area [14], and that the transition from the inner to the outer myometrium is gradual with no clear demarcation [14].

It is thought that the inner myometrium is responsible for supporting sperm transport and the retention of the blastocyst prior to implantation. The inner myometrium may also have a role in aiding the separation of endometrial functionalis [15] and possibly in the regulation of uterine blood loss during menstruation [16].

In rodent pregnancy the two muscle layers have clear and different roles. The circular muscle is responsible for maintaining the fetal units as separate entities and assisting with parturition [17] whilst the longitudinal muscle aids the correct positioning of the fetal units within the uterus and retraction of the cervix towards the oviducts during parturition.

It has been suggested that the inner myometrium of the non-pregnant uterus (in rodents and human) aids sperm transport from the region of the cervix [15, 18]. This may be triggered by prostaglandins and other inflammatory mediators in the ejaculate. The resulting sporadic contractions of the inner myometrium create negative intra-uterine pressures that draws the sperm into the uterine cavity where it binds to pinopodes on endometrial epithelial cells [19]. Sexual stimulation and the release of oxytocin results in more coordinated and forceful uterine contractions creating a peristaltic wave from the cervix towards the oviduct and these contractions position the sperm closer to the oviduct where a relatively small number migrate for fertilisation to take place [20].

An alternative mechanism postulates that, in the female, an intrinsic contractile feedback response during intercourse increases the stimulation of the purinergic and neurotrophin-sensitive neurones that innervate the outer myometrium. This, in turn, stimulates the entire uterus to contract and thus move sperm towards the oviduct. Simultaneously, the release of mediators associated with ‘pleasure’ stimulates the basal cilial receptors which aid sperm progression in the oviduct from the isthmus to the ampulla. Endocannabinoids, which increase ciliary beat frequency and sperm motility in vitro, may have a role in this process [21]. A similar mechanism may be involved in retrograde uterine transport of endometrial tissue during menstruation and this may be a factor in the pathogenesis of endometriosis [22].

The uterus is a unique organ in that its primary role of holding and nurturing the developing fetus is concerned with the preservation of the species rather than the survival of the individual. For pregnancy to be successful, the process requires coordinated sequential changes. The changes that occur in the myometrium during the earlier synthetic stage of pregnancy are relatively slow when compared to the changes associated with the contractile stage that occurs at the end of pregnancy and during the perinatal period.

Health information websites report that during the normal menstrual cycle most patients with adenomyosis have no outward symptoms, and can pass their entire reproductive life with asymptomatic adenomyosis, whilst the medical literature reports that only 35–40 % of women are asymptomatic [42]. Adenomyosis can be associated with a range of concomitant pathology including endometriosis and fibroids. The peak incidence of adenomyosis occurs in the fourth decade of life [43] and many women with adenomyosis also have endometriosis, which may itself account for symptoms of dysmenorrhoea, infertility and possibly menorrhagia. There is some evidence of heightened central nervous system sensitivity in some women with adenomyosis, resulting in heightened pain perception, presumably because the myometria of women with adenomyosis have increased numbers of sensory neurones. This increase in neuronal density is dependent upon local production of neurotrophins and their cognate receptors [44] and an altered expression of the neurotrophins NGF and BDNF and their cognate receptors have been reported in the myometrium in women with adenomyosis [45, 46]. This is in line with previous reports of increased nerve growth factor expression and changes in the lower affinity neurotrophin receptor (p75NTR) in the mouse model of adenomyosis [47].

PGP9.5 immunoreactivity was identified in the functional layers of the endometrium in women with adenomyosis and fibroids who also had pain symptoms but not in women without pain [48]. PGP9.5 nerve fibre density in the basal layer of the endometrium and in the myometrium was also significantly increased in women with pain [48]. It was hypothesised that dysmenorrhoea linked to adenomyosis may result from bleeding within the adenomyotic nodules in response to steroid withdrawal at menstruation, although entrapped blood is not commonly observed in affected uteri. Many of the ligands and receptors for the neurotrophin family of proteins have been shown to increase under the influence of oestradiol [49] which has been implicated in the aetiology of adenomyosis [47].

If the propagation of myometrial contractility and function is dependent on the production of a complete syncytium, then the presence of adenomyotic lesions may affect the normal physiology of the myometrium by interfering with the transfer of small molecules through the gap junctions produced by connexin proteins or by interrupting the propagation of membrane depolarisation through the muscle fibres. In women with adenomyosis, this might impair sperm transport [50], reduce fertility [51, 52], increase first trimester miscarriage [52, 53], increase the incidence of preterm labour [54] and precipitate placental abnormalities [55]. Recent research has found that women with adenomyosis undergoing IVF/ICSI treatment for infertility have higher miscarriage rates than women without the condition, with lower pregnancy rates and a much higher risk for early pregnancy loss [54]. Affected women also appear to have an increased risk of premature labour and placental abruption [55]. This suggests a dysfunctional myometrium. Another serious but rare complication of adenomyosis in pregnancy is the risk of uterine rupture during labour [56]. This may be due to aberrant decidualisation of deep lesions resulting in a reduced myometrial mass leading to rupture under tension. However, the majority of women with adenomyosis do become pregnant with normal outcome, suggesting that sperm transport may not be significantly affected by adenomyosis. But fertility rates measured by on-going pregnancy (but not biochemical pregnancy) in assisted reproduction are lower in adenomyosis [57], suggesting that impairment of blastocyst retention rather than in sperm delivery and fertilisation occurs in these women.

Whether there is altered decidualisation in adenomyosis remains uncertain [58]. Preliminary data demonstrated no impairment of in vivo decidualisation of stromal cells derived from adenomyosis as evidenced by normal production of prolactin and insulin-like growth factor binding protein-1 (IGFBP-1) (Fig. 4.3). It is possible that lower on-going pregnancy rates results from inner myometrial hyperperistalsis or dysperistalsis [59], resulting in disruption of implantation, perhaps under the influence of the increased production of nitric oxide [60].

Ectopic pregnancy rates may not be increased in women with adenomyosis suggesting normal transport of the zygote through the oviduct, but ectopic pregnancy has been linked to adenomyosis in smokers [61] and a case was reported of an intramural pregnancy linked to adenomyosis [62], although such cases must be extremely rare. Caesarean section rates are not significantly increased in women with adenomyosis and affected women do not experience prolonged labour [61], however, myometrium affection varies significantly depending on the extent of the disease and further research is needed to correlate disease spread and its impact.

Despite recent technological advances, there remains a paucity of information on many important aspects of uterine physiology and on the impact of adenomyosis. Even though research on the functioning of the myometrium in pregnancy is moving at a steady pace, our understanding of the role of the myometrium during the non-pregnant state remains limited.