Suppression of Serum Prolactin Levels after Sports Concussion with Prompt Resolution Upon Independent Clinical Assessment To Permit Return-to-Play

Concussion is a complex pathophysiological process affecting the brain as a result of traumatic biomechanical forces. ¹ According to Walker's explanation of the physiological basis of concussion, a concussive insult to the brain results in transient, widespread perturbations of cortical membranes that ultimately favor neuronal excitation. ² This description has since been characterized as that of a marked outflow of neurometabolites and excitatory neurotransmitters whose concentrations do not resolve to pre-injury levels for several hours, if not days following the event. ³ These cellular changes in the acute post-injury period are unobtainable by direct observation in humans and as such, require indirect evidence from end-organs or systems that are sufficiently sensitive to these pathological central neuronal membrane changes.

A meta-analysis determined a pooled prevalence of anterior pituitary deficiency of 27.5% following traumatic brain injury, ⁴ and a recent report in retired athletes demonstrated that a more significant history (i.e., increased frequency) of concussive head trauma was associated with growth hormone (GH) failure in later life. ⁵ Overt manifestations and clinical syndromes of pituitary dysfunction have been demonstrated to occur in the post-concussive and chronic mild traumatic brain injury (mTBI) state; limited evidence for pituitary dysfunction after single, multiple, or persistent concussion injury is highlighted by reports of reduced pituitary volume, ⁶ GH deficiency ⁷ and diabetes insipidus. ⁸ The premise to consider, then, is that if GH deficiency represents one of the more common pathological endpoints in the function of the hypothalamic-pituitary axis among individuals with a significant past medical history of concussion, then perhaps some objective evidence of pituitary disturbance may be present immediately after the concussive event, and, if repeatedly evaluated upon successive brain insults throughout life, may be a useful pathophysiological marker for the genesis and/or progression of pituitary hormone deficiency states. Thus, if pituitary dysfunction is a potential long-term medical consequence of concussion or mTBI, what evidence exists in the acute post-concussive state to demonstrate a pathophysiological process? A dearth of empirical evidence (i.e., circulating biomarkers) to support the genesis of these long-term outcomes has yet to be identified in the acute or sub-acute phase of injury.

Insight to facilitate transition from bench to bedside may be provided by the observation of elevated dopamine concentrations in the rodent brain after experimental concussion. ⁹ Dopamine is a neurotransmitter with numerous targets in the central nervous system, including the hypothalamus, that, when activated, will result in a reciprocal change of serum prolactin (PRL) concentration. Thus, if cortical/neuronal excitation is present and central dopaminergic activation of the hypothalamus is elevated in the sub-acute period following concussion, then biomarkers from this activation may be accessible for the potential diagnosis and clinical monitoring of concussion. We present changes in the serum PRL concentration during the first 2 post-injury weeks following concussion in four male athletes.

As a component of a research protocol approved by our institutional review board, venous blood samples were obtained between 8 and 11 am in four male intercollegiate athletes (age, 20 ± 1 years; height, 71 ± 5 inches; weight, 174 ± 21 pounds) within 48 h (V1) of sustaining a concussion and, again at 7 (V2) and 14 (V3) days. Upon collection, blood samples were spun and separated according to standard practices, and serum was immediately stored frozen until sent to a commercial laboratory for assay (Quest Diagnostics, Teterboro, NJ). The serum PRL concentrations were then categorized by quartile (Q) for each study visit using previously described limits within the normal expected range for males (2-18 ng/mL): Q1 (< 5 ng/mL); Q2 (5.1–7 ng/mL); Q3 (7.1–11 ng/mL); and Q4 (11.1–34.9 ng/mL). ¹⁰ Upon intake, the athletes self-reported that the current injury was their first diagnosed concussion, were free of pre-existing medical conditions, denied the use of psychotropic agents that could potentially confound the study outcomes, and had not engaged in vigorous physical activity since being injured (i.e., a period of 40–48 h). All athletes received standard medical care by appropriately qualified sports medicine professionals, which included progressive evaluation for safe return-to-play. ¹¹ Written informed consent was obtained prior to the initiation of study procedures.

PRL concentrations in these four male athletes were reduced between ∼50–500% at V1 compared with V3, when the concussion injury symptoms had resolved. Each athlete demonstrated rising PRL concentrations throughout the normal range upon successive study visits (Fig. 1). The athlete with the lowest PRL (Q1: 2.4 ng/mL) on V1 complained of sexual dysfunction and loss of libido, symptoms consistent with coincident hypogonadism, which also resolved as PRL concentrations increased and symptoms of concussive injury abated by V3. Conversely, the athlete with the highest PRL at V1 (Q3: 9.0 ng/mL) was symptom-free within 2 days of concussion and cleared to resume athletic participation. The remaining athletes followed a typical resolution of somatic and cognitive symptoms and were cleared for participation by V2 and V3, respectively. A provocative, and potentially useful, observation was that no athlete was cleared to return-to-play until the PRL concentration entered Q4 from their witnessed nadir at V1.

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FIG. 1.

Serum prolactin concentrations in four male athletes following concussion at three post-injury time-points: V1 (within 48 h), V2 (7 days post-injury), and V3 (14 days post-injury). The number of days after injury until being cleared for full sports participation appears at the beginning of each subject data line.

Direct evidence for the role of PRL in the post-concussive state is limited, as is any potential functional implication of dopamine. In moderate-severe brain injury, elevated PRL is not uncommon following injury and anatomical trauma to the pituitary stalk is speculated to have occurred, leading to attenuated/ablated dopaminergic tone. ^{12 –14} However, after sports-related concussion, where a functional disturbance of central dopaminergic tone (possibly caused by the outpouring of excitatory neurotransmitters) to an anatomically and functionally intact hypothalamic pituitary axis could be speculated to have occurred, serum PRL concentrations increased from lower quartiles within the normal range and transitioned through higher quartiles across 2 weeks of observation as the concussive injury resolved clinically and the athletes were able to resume sporting activities. It may be speculated that transient augmentation of central dopaminergic tone to the hypothalamus may have resulted in a greater inhibition of PRL secretion early after concussion and that disinhibition of PRL release may have occurred when central dopaminergic tone subsequently returned to pre-injury levels.

This novel observation provides preliminary indirect evidence for dopaminergic and pituitary dysfunction during the first 2 weeks after concussion. Alternatively, however, some of the observed concentrations may have been influenced by other factors that were minimally controlled for in our study. Intrinsic PRL secretion follows a circadian pattern wherein circulating concentrations are the highest during sleep and lowest during the waking hours, with the nadir often occurring before noon. ^{15 –18} All of our participants were evaluated when this daily nadir was expected to have occurred. Acute bouts of exercise have been demonstrated to result in a marked elevation of PRL and are anticipated to return to basal levels within hours of discontinuation. ¹⁹ On the other hand, the transition to a deconditioned state (i.e., transition from end-of-season fitness to off-season) has shown to have no appreciable impact on PRL concentrations. ²⁰ All athletes were observed within 48 h of sustaining the injury; in each case, the athlete sustained the injury in the evening or afternoon during a game, and was evaluated no later than the second morning after injury. Therefore, no athlete had engaged in strenuous exercise for a period of 40–48 h, rendering the impact of an acute bout of exercise, which would have served to increase PRL concentrations, minimal. Similarly, no athlete was involved in a practice/exercise session prior to the study visit or blood sample collection. As yet to be identified effects of concussion and its neurometabolic cascade also may have influenced the observed PRL concentrations. Further work to confirm and extend the implications of this observation of PRL changes following concussion in a case–controlled setting with pre-injury evaluation is needed, as is the parallel determination and potential relationship of serum PRL levels after concussion injury to those of serum GH and possibly other pituitary hormones.