Screening for Occult Maternal Conditons in Infertility Patients

Sarah L. Berga *, James Robert McCord Professor and Chairman ,


Stress is a generic term for a state of psychosocial disharmony and connotes a panopoly of meanings. Physiologically stress is understood as activation of processes in response to events and conditions. Acute stress is associated with brief behavioral challenges that elicit adaptive neuroendocrinologic responses termed “homeostatic” that promote short-term survival. Chronic stress is associated with prolonged behavioral challenges. The neuroendocrinologic adaptations associated with chronic stress and protracted behavioral challenge are termed “allostatic.” Allostasis is the achievement of stability through change and entails the alteration of the feedback “set point” for a given neuroendocrine arc. Reproductive “alignment” occurs when physiological responses elicited by the external milieu modulate reproductive processes. A variety of factors serve as determinants and mediators of reproductive alignment. Because factors interact the independent impact of any one factor may be minimal and difficult to discern. Indeed a constellation of factors determines whether reproduction is promoted or impaired. Reproductive processes subject to environmental modulation include ovulation fertilization embryogenesis implantation placentation and parturition. Clinical manifestations of reproductive misalignment include infertility recurrent miscarriage intrauterine growth restriction preterm labor low birth weight preeclampsia and congenital birth defects. Mechanisms mediating these outcomes include alteration of physiological patterns of the hypothalamic-pituitary-adrenal (HPA) and -thyroidal (HPT) axes and alteration of genetic patterns such as methylation of DNA. Physiological processes are generally viewed as plastic and reversible. While epigenetic alterations may be to some extent reversible they also may be generationally transmitted. The term “fetal origins of adult disease” connotes disease or disorders due to transmissible epigenetic imprinting and underscored the notion that health promotion and predictive health begins before birth. Not all maternal or paternal conditions that can compromise fetal well-being are readily recognized and include endocrine conditions such as subclinical hypothyroidism impaired glucose tolerance and diabetes autoimmunity infections and genetic status. Stress is often an unappreciated cause of reproductive compromise and is difficult to recognize. While stress is generally categorized as metabolic or psychogenic strictly speaking these are not separable entities. Behaviors that activate stress signaling pathways activate pathways subserving metabolic and psychogenic outputs. Chronic activation of the HPA and/or suppression of the HPT can impede hypothalamic-gonadal function in both men and women. Individuals with functional hypothalamic hypogonadism typically display a combination of behaviors in response to ongoing psychogenic challenge that concomitantly induce mild energy imbalance and in the context of chronic adrenal activation increase the metabolic costs of common activities including recreational exercise. Stress-induced anovulation (SIA) also referred to as functional hypothalamic amenorrhea (FHA) provides a classic and overt example of reproductive compromise and is characterized by the cessation of menses and infertility. SIA is accompanied by a constellation of neuroendocrine secretory aberrations and psychological correlates that include unrealistic expectations of self and others perfectionism and maladaptive attitudes about body image and food. However SIA represents only a small portion of the possible presentations for reduced gonadal function in women. Other less overt forms of reproductive compromise are far more prevalent and include polymenorrhea (menstrual interval < 24 days) oligomenorrhea (menstrual interval > 35 days) and luteal insufficiency with preserved menstrual interval. Occult reproductive compromise may only come to clinical attention if fertility is desired especially in men. While it is generally appreciated that maternal health impacts fetal health the exact mechanisms mediating this link remain to be fully explicated. One must also recognize that factors with the potential to influence reproductive processes are not limited to those contributed by the parents. Medical interventions intended to facilitate reproduction also have the potential to activate these mechanisms. Thus while assisted reproductive technologies allow us to bypass many of the mechanisms that mediate reproductive compromise they also alter the developmental milieu during fertilization and early embryogenesis.