Progesterone Response in Neonatal Endometrium is Key to Future Reproductive Health in Adolescents

“Two major issues involving reproductive organs in young girls are adolescent pregnancy and early-onset endometriosis.”

Physicians, even those treating adolescents, often are not familiar with uterine and ovarian functions and this lack of understanding of reproductive medicine, coupled with other factors, is often responsible for less than optimal care; yet, healthcare focused on the adolescent girl and her needs should be one of the cornerstones of correct management. Two major issues involving reproductive organs in young girls are adolescent pregnancy and early-onset endometriosis.

With regard to adolescent pregnancy, a classical concept considers gynecological age as an indicator of biological immaturity with a risk factor for a poor pregnancy outcome, especially preterm delivery and pre-eclampsia [1,2]. However, in recent years, the concept of ‘biological immaturity’ has been further defined, with the discovery of an important feature: the persistence in some adolescents of a certain degree of the ontological progesterone resistance [3] present at birth in the majority of neonates [4]. This phenomenon may impact on the outcome of pregnancy in early adolescence.

Concerning early-onset endometriosis (that affecting adolescent girls), its characteristics have now been investigated in a number of clinical series and its main features seem well established [5,6]. A major issue with this disease is that its diagnosis is often delayed in spite of the early appearance of complaints of dysmenorrhea or acyclic pelvic pain [7]. This makes it imperative to improve our diagnostic ability in the presence of symptoms allowing a suspect of endometriosis in an adolescent. While so far none of the potential markers for the diagnosis of endometriosis have been found to be clinically applicable, the phenomenon of neonatal uterine bleeding (NUB) observed in approximately 5% of all neonates [8–11] is worth to be investigated as a clinical marker of increasing risk of adolescent endometriosis.

In view of what precedes, there is a concrete possibility that neonatal events may influence adolescent reproductive functions; for this reason, it seems important to evaluate the fetomaternal conditions that affect the maturation of the endometrial progesterone response in the neonate, since they are likely to be key factors for the future reproductive health of individual neonates.

The first menstruation as a sign of maturity & distress

An extensive search of the forgotten literature on the occurrence and significance of NUB in the neonate revealed a large number of papers published in European journals between 1822 and 1985. They include case reports and case series on uterine bleeding and two endometrial studies by pathologists. More than a century ago, Halban [12] explained his use of the expression ‘neonatal menstruation’ to describe NUB due to the presence of a similar endometrial response with decidualization as in adult menstruation. Several clinical studies performed in Europe described ‘visible’ neonatal bleeding occurring 2 to 4 days after birth and lasting for 3–5 days. They also detailed the presence of ‘occult’ bleeding detected by chemical or cytological means in 25–60% of the newborn [8–11]. Interestingly, a large study conducted in all females newborn in Novi Sad (Serbia) demonstrated a significant increase of visible bleeding in case of postmaturity [11]. Another study conducted in Strasbourg found that the percentage of visible bleeding may rise to more than 40% in the presence of fetomaternal factors affecting the well-being of the newborn, such as maternal hypertensive disease, fetomaternal blood incompatibility and low birth weight [8].

The spectrum of progesterone responses in the neonatal endometrium

It has been known for half a century that progesterone synthesized by the human placenta [12] rises during pregnancy in the fetal circulation to very high values due to the dehydrogenase activity of the endothelial cells of the placental circulation [13]. In spite of this, in term fetuses and newborns the endometrium fully responds to progesterone by decidualization and menstrual-like shedding in only 5% of the cases; an early progesterone response characterized by subnuclear vacuolization was observed in 28%, whereas the absence of any progesterone response was evident in the majority of neonates [4]. Given this situation, we can speculate that the spectrum of progesterone responses observed in the neonatal endometrium – ranging from a fully responsive endometrium resulting in menstrual-like bleeding and a total progesterone resistance – probably persists till the onset of menarche. Under such circumstances full progesterone response with neonatal menstruation may be linked with pelvic endometriosis during adolescence; on the other hand, a persisting degree of progesterone resistance of the endometrium after menarche may be linked, in case of juvenile pregnancy, with defective deep placentation increasing the risk of major obstetrical disorders, such as pre-eclampsia, fetal growth restriction and preterm birth.

Endometrial menstrual-like shedding in the neonate as cause of early-onset endometriosis

The hypothesis that neonatal menstrual-like bleeding is similar to cyclic menstrual bleeding, a cause of pelvic endometriosis, is supported by several observations:

The anatomical structure of the neonatal uterus with a corpus/cervix ratio of 1:3 is likely to cause a functional outflow obstruction and favors menstrual reflux with peritoneal seeding of endometrial stem/progenitor cells [14–16]. Indeed, neonatal endometriosis has been documented in an autopsy case of a neonate [17];

Neonatal endometrial shedding is likely to contain abundant endometrial stem/progenitor cells able to implant on the peritoneum and ovaries [16];

Approximately a third of the neonates are exposed to some form of uterine bleeding and reflux of endometrial shedding which is in agreement with the generally estimated incidence of endometriosis in adult women [8–11];

The neonatal origin hypothesis explains the occurrence of endometriosis in premenarcheal girls, as well as the severity in some young adolescents [5,18];

Morphological features of peritoneal and ovarian implants, namely superficial, angiogenic and hemorrhagic lesions with adhesions, are similar in premenarcheal, adolescent and young girls [5,18].

For these reasons, as for adult menstruation, the neonatal menstruation can be proposed as a cause of early-onset endometriosis. Obviously, proof that NUB is a cause of endometriosis can only be demonstrated by prospective studies of neonates after the phenomenon is systematically recorded in obstetrical or neonatal notes.

Progesterone-resistant neonatal endometrium & risk of pre-eclampsia in adolescent pregnancy

The concepts of ‘ontogenetic progesterone resistance’ [3] and ‘menstrual preconditioning’ [19] infer that the human uterus starts out as a relatively immature organ that acquires the competence of deep placentation in response to dynamic remodeling events triggered by menstruation, miscarriage or parturition. Menstruation may not have been an evolutionary coincidence, but serves to protect uterine tissues from the profound hyper-inflammation and oxidative stress associated with deep placentation. This process of preconditioning provides a novel paradigm for understanding how reproductive disorders impact on pregnancy outcomes [20,21].

The majority of neonates are born with a relative endometrial progesterone resistance and it is likely that this resistance persists till menarche. In case pregnancy occurs at a stage of residual endometrial progesterone resistance, decidualization and deep placentation may be affected. Indeed, it has been noted that the risk of pre-eclampsia in an adolescent is greater, the younger the age at the time of pregnancy [1,2].

Conclusion

Progesterone response in neonatal endometrium represents a spectrum with, on the one hand, fully progesterone responsive endometrium resulting in menstrual-like bleeding in the neonate, and, on the other hand, ontogenic progesterone resistance that may persist till the onset of menarche. It can be assumed that endometriosis at least in the adolescent is caused by neonatal menstrual-like bleeding with tubal reflux and pelvic seeding of endometrial progenitor cells. Conversely, endometrial progesterone resistance may persist till adolescence when cyclic menstruations constitute the preconditioning mechanism for achieving a progesterone responsive endometrium. In the absence of full progesterone response, any pregnancy occurring early in the adolescence may result in defective deep placentation causing major obstetrical disorders such as pre-eclampsia, low birth weight or preterm birth.

The challenge today is twofold: first and foremost, to test the hypothesis by prospective studies aiming at ascertaining whether progesterone response of the neonatal endometrium is the key factor for reproductive health in the adolescent. The observation of the ‘little bleeding from the vagina’ described by lay press as perfectly normal should be carefully recorded as a unique clinical marker of fetal distress. The sooner the registration of the presence or absence of neonatal uterine bleeding starts the better, as it takes at least two decennia to know the results.

Second, to try and identify any report, no matter how old, on endometrial progesterone response or uterine bleeding in the neonate, to strengthen (or begin to confute) the new theory.