The term ‘reproductive alignment’ denotes the concept that reproductive status will reflect and be aligned with the physiological status of an individual and thereby his or her external environmental milieu. Reproduction is an incredibly energy-dependent process that requires significant metabolic resources to accomplish. It should be of no great surprise, then, that our bodies have evolved signaling systems that communicate to our brain our energetic and psychological status and readiness for reproduction. The brain, in turn, has mechanisms for responding to the various signaling systems and altering reproductive competence to thereby ensure reproductive alignment. In the final analysis, reproductive alignment depends on neural mechanisms.
It is not an exaggeration to say that the menstrual cycle begins with the brain. We know that the gonadotropin-releasing hormone (GnRH) pulse generator is localized to the hypothalamus, an area that receives signaling from the periphery and the rest of the brain, and that the GnRH signal amplitude and frequency drive the pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone. Further, the GnRH pulse generator is not an ‘on/off’ switch, but rather operates much like a rheostat. Indeed, while the GnRH pulse generator is active during fetal life, thereafter it is modulated by a huge variety of substances, not all of which have been identified, so that from the beginning there is reproductive alignment with chronological age and developmental stage. For ontological reasons, the GnRH pulse generator is suppressed or desynchronized shortly after birth until the time of puberty and this represents an example of chronological reproductive alignment. During the reproductive years, we often assume that the GnRH generator is subject to only minimal modulation. For instance, we know that as the follicle develops and the mid-cycle of the menstrual cycle approaches, there is amplification of GnRH pulse amplitude and pulse frequency until such time as a GnRH surge results in a LH surge or until the amplified GnRH drive provokes a pituitary LH surge (independent of a GnRH surge). Progesterone slows the frequency of the GnRH pulses but heightens the amplitude. Intermediate steps, such as opioids and γ-aminobutyric acid (GABA), may be involved in producing this effect of progesterone.
What other factors modulate GnRH drive to the reproductive axis before menopause and after puberty? Limited data suggest that leptin and other adipokines, insulin, opioids, corticotroin-releasing hormone, cortisol, GABA, serotonin and other neurotransmitter systems directly or indirectly modulate GnRH activity, including both pulse frequency and amplitude. In so doing, these signaling systems collaboratively convey information about reproductive readiness and alignment. There is even the possibility that the brain and GnRH signaling system can be imprinted during fetal life by maternal or fetal signals. If so, this would suggest a degree of plasticity and reproductive alignment not heretofore widely appreciated.
It is important to consider the role of mechanisms mediating reproductive alignment when seeing patients with infertility and menstrual cycle disorders. Much of what we view as disease may reflect reproductive alignment in the face of reversible metabolic or psychogenic challenge. Even polycystic ovary syndrome may be viewed as a now obsolete adaptive mechanism for allowing fertility during chronic energy deficiency. An enhanced appreciation of the role of the brain in mediating reproductive alignment is critical for determining the appropriate intervention for our patients with infertility and menstrual cycle disorders.