Impact of Hemorrhagic Shock on Pituitary Function

Accepted Manuscript Impact of Hemorrhagic Shock on Pituitary Function Bellal Joseph, MD, FACS, Ansab A. Haider, MD, Viraj Pandit, MD, Narong Kulvatunyou, MD, FACS, Tahereh Orouji, MD, Mohammad Khreiss, MD, Andrew Tang, MD, FACS, Terence O’Keeffe, MD, Randall Friese, MD, FACS, Peter Rhee, MD, FACS PII:

S1072-7515(15)00181-7

DOI:

10.1016/j.jamcollsurg.2015.02.026

Reference:

ACS 7810

To appear in:

Journal of the American College of Surgeons

Received Date: 6 January 2015 Revised Date:

18 February 2015

Accepted Date: 18 February 2015

Please cite this article as: Joseph B, Haider AA, Pandit V, Kulvatunyou N, Orouji T, Khreiss M, Tang A, O’Keeffe T, Friese R, Rhee P, Impact of Hemorrhagic Shock on Pituitary Function, Journal of the American College of Surgeons (2015), doi: 10.1016/j.jamcollsurg.2015.02.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Impact of Hemorrhagic Shock on Pituitary Function

Bellal Joseph, MD, FACS, Ansab A Haider, MD, Viraj Pandit, MD, Narong Kulvatunyou, MD,

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FACS, Tahereh Orouji, MD, Mohammad Khreiss, MD Andrew Tang, MD, FACS, Terence O’Keeffe, MD, Randall Friese, MD, FACS, Peter Rhee, MD, FACS

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University of Arizona Medical Center, Tucson, AZ.

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Division of Trauma, Emergency Surgery, Critical Care, and Burns; Department of Surgery,

Disclosure Information: Nothing to disclose.

Support: Departmental research funds of the Division of Trauma at University of Arizona.

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Presented at the Academic Surgical Congress, Las Vegas, NV, February 2015

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Correspondence address: Bellal Joseph, MD University of Arizona Department of Surgery Division of Trauma, Critical Care, And Emergency Surgery 1501 N. Campbell Ave, Room.5411 P.O. Box 245063 Tucson, AZ 85724 E-mail: [email protected] Tel 520-626-5056 Fax 520-626-5016

Running head: Hormonal Variation in Hemorrhagic Shock

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ABSTRACT BACKGROUND: Hypopituitarism after hypovolemic shock is well established in certain patient cohorts. However; the effects of hemorrhagic shock (HS) on pituitary function in trauma

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patients remains unknown. The aim of this study was to assess pituitary hormone variations in trauma patients with HS.

STUDY DESIGN: Patients with acute traumatic HS presenting to our level 1 trauma center

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were prospectively enrolled. HS was defined as systolic blood pressure (SBP) ≤ 90 mm Hg on arrival or within 10 minutes of arrival in the ED, and requirement of ≥ 2 units of packed red

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blood cell transfusion. Serum cortisol and serum pituitary hormones [vasopressin (ADH), adrenocorticotrophic hormone (ACTH), thyroid stimulating hormone (TSH), follicular stimulating hormone (FSH), and luteinizing hormone (LH)] were measured in each patient on admission and at 24, 48, 72,and 96 hours after admission. Outcome measure was: variation in

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pituitary hormones.

RESULTS: A total of 42 patients were prospectively enrolled with mean age 37±12 years, mean SBP 85.4+64.5 mm of Hg, and median injury severity score 26 [18-38]. There was an increase in

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the levels of cortisol (p<0.001), decrease in the levels of ACTH (p<0.001) and ADH (p<0.001), but no change in the levels of LH (p=0.30), FSH (p=0.07) and TSH (p=0.89) over 96 hours. Ten

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patients died during hospital stay. Patients who died had higher mean admission ADH levels (p=0.03), higher mean admission ACTH levels (p<0.001), and lower mean admission cortisol level (p=0.04) compared to patients who survived. CONCLUSIONS: Acute hypopituitarism does not occur in trauma patients with acute hemorrhagic shock. In patients who died, there was a decrease in cortisol levels, which appears to be adrenal in origin.

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INTRODUCTION: Trauma and its associated complications remain a major cause of morbidity and mortality world wide, with hemorrhagic shock being the most common cause of mortality in trauma patients.1,2

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Stress hormones like cortisol and ADH play a vital role in maintaining homeostasis following hemorrhage; this role requires a functioning hypothalamic-pituitary-adrenal axis.3,4 Previous studies have reported that disruption of this axis impedes the body’s ability to respond to stress

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and leads to worse outcomes.5-8

Hypopituitarism is a well-known complication that can follow conditions like childbirth,

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radiation, surgery, and head trauma. Severe post partum hemorrhage resulting in hypopituitarism is referred to as Sheehan’s syndrome, and is due to the ischemic necrosis of the pituitary gland from shock9. Posttraumatic hypopituitarism usually follows traumatic brain injury (TBI) and may affect up to 40% as an isolated pituitary hormone deficiency.10 Also, there have been reports of

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infarctions of the pituitary following trauma other than TBI.11,12 The presence of pituitary infarctions in the absence of TBI suggests that traumatic transection of the pituitary stalk may not be the only mechanism involved in posttraumatic hypopituitarism. Other mechanisms such as

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anoxia from hemorrhagic shock have been proposed for this. However, most of the literature is limited to anterior pituitary gland function and there is lack of evidence on whether pan-

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hypopituitarism truly occurs following hemorrhagic shock.13 Recently, some studies have also described an abnormal adrenal response following hemorrhagic shock, however whether this dysfunction is from adrenal or pituitary origin remains unknown.8,14 The aim of our study was to look at the variability and changes in pituitary and cortisol

levels following hemorrhagic shock from trauma. Pituitary and adrenal hormone assessment may provide insight into pituitary adrenal axis response following hemorrhagic shock.

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METHODS: After the approval from the Institutional Review Board at the College of Medicine at the University of Arizona, we performed a prospective observational study to evaluate the pituitary

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hormones and cortisol levels in trauma patients presenting with hemorrhagic shock(HS). HS was defined as systolic blood pressure (SBP) ≤ 90 mm Hg on arrival or within 10 minutes of arrival in the ED and requirements of ≥ 2 units of packed red blood cell transfusion during initial

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resuscitation in the ED. Patients who met the inclusion criteria were enrolled into the study after an informed consent was obtained from the patient or their legal authorized representative within

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the first 24 hours of arrival.

Patients transferred from other institutions, patients with traumatic brain injury (positive intracranial hemorrhage on head CT scan), and patients dead on presentation were excluded from the study.

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Blood from the patients who met the inclusion criteria was drawn at the time of admission (0 hours), and at 24, 48, 72, and 96 hours after admission to evaluate serum cortisol and serum pituitary hormones [vasopressin (ADH), adrenocorticotrophic hormone (ACTH),

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thyroid stimulating hormone (TSH), follicular stimulating hormone (FSH), and luteinizing hormone (LH)] levels. Additionally, we prospectively recorded the following data points in each

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patient: patient demographics (age, gender, race), admission vital parameters (systolic blood pressure (SBP), massive transfusion (≥10 units of PRBC in first 24 hours, heart rate (HR), temperature), Glasgow coma scale (GCS) score, admission laboratory parameters (hemoglobin, platelet counts, international normalized ratio [INR], lactate, base deficit), units of blood products transfusion, and in-hospital mortality. The injury severity score (ISS) and mechanism of

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injury were obtained from the trauma registry. A sub analysis was performed to look for differences between the survivors and non-survivors. Our outcome measure was variation in pituitary hormones and cortisol levels of patients

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over time at 0, 24, 48, 72 and 96 hours after hemorrhagic shock. Relative and severe acute

adrenal insufficiency were defined as 0 hour serum cortisol level less than 25 µg/dl and 10 µg/dl respectively.8

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Data are reported as the mean ± standard deviation (SD) for continuous descriptive variables, as the median [range] for ordinal descriptive variables and as the proportion for

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categorical variables. Continuous data was analyzed using Student t test and Mann Whitney U test. Pearson’s chi square test and Fischer’s exact test were used to compare categorical variables. Polynomial Analysis of Variance (ANOVA) was performed and post hoc analysis with Bonferroni correction was used to assess for difference in the level of bio-makers at different

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time points. Student t test was used to compare the mean difference in hormone levels between the two groups (survivors and non survivors) at 0 hours. For our study, we considered p value < 0.05 as statistically significant. All statistical analyses were performed using the Statistical

RESULTS:

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Package for Social Sciences (SPSS, Version 21; IBM, Inc., Armonk, NY).

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During the study period, a total of 47 patients were prospectively enrolled of which, 42 were included in the study. Of the five patients that were excluded, two patients were transfers from other hospital, and three patients had an intracranial hemorrhage. Of the 42 patients included in the study, mean age was 37±12 years, 81% (n=34) were

male, mean admission SBP was 85.4 ± 64.5 mm of Hg, and median ISS was 26 [18-38]. Table 1 demonstrates the demographic details of the study population.

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The mean admission hemoglobin of the population was 12.6 ± 5.2, mean INR was 1.5 ± 1.2, mean PRBC units transfused during the first 24 hours were 7.7 ± 4.9, and 51.8% (n=20) patients required massive transfusion. Table 2 describes the initial laboratory findings and

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management of our study population.

Change in pituitary hormone and cortisol levels from 0 to 96 hours

Statistical analysis was performed for 36 patients [32 survivors and 4 non-survivors] with

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hormones level recorded for the total period of 96 hours. There was a significant decline in the levels of serum ACTH (40.6 ± 8.3 pg/ml vs. 31.3±11.5 pg/ml; p<0.001) and ADH (19.2 ± 6.4

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pg/ml vs. 8.6±5.2 pg/ml; p<0.001) at 96 hours compared to that at 0 hour. There was no difference in the levels of LH (11.2±5.6 mIU /ml vs. 10.9±5.4 mIU /ml; p=0.30), FSH (9.4±3.0 mIU /ml vs. 7.3±4.4 mIU /ml; p=0.07) and TSH (1.42±0.6 µIU /ml vs 1.6±0.5 µIU /ml; p=0.89) between 0 to 96 hours. The levels of serum cortisol increased significantly from 20.9±9.8 µg/dl

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at 0 hour to 32.2±14.0 µg/dl at 96hr (p<0.001) Figure 1 represents the variation in mean hormone levels in these patients over the 96-hour period. In-hospital mortality was 24% (10/42) in our population. Of the patients who died in the

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hospital, four died during the first 24 hours, two patients died between the 24-48 hours, while the remaining four died after 96 hours of hospital admission.

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A sub-analysis was performed to compare the differences between survivors and non-

survivors. Tables 1 and 2 compare the demographics, laboratory parameters and initial management between the two groups. Difference in trends of hormone levels between survivors and non-survivors Among patients that survived (n=32), there was an increase in cortisol levels (21.2±9.9 µg /dl vs. 35.5±11.3 µg/dl; p<0.001) from 0 to 96 hours while there was a decrease in ACTH (39.1±7.3

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pg/ml vs. 29.3±10.5 pg/ml, p<0.001) and ADH (19.1±6.7 pg/ml vs. 8.1±5.1 pg/ml, p=0.003) levels over the same time period. On the other hand, the levels of LH (p=1.00), FSH (p=0.09), and TSH (p=1.00) remained unchanged. (Figure 2)

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In the non-survivors, there was a significant decline in the level of cortisol (14.3±7.1 µg /dl vs. 6.3±0.6 µg /dl; p=0.03) between 0 and 96 hours. However; the levels of ACTH (p=0.37), LH (p=0.38), FSH (p=0.06), and TSH (p=1.00) remained unchanged at 96 hours compared to the

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initial recording at 0 hours. (Figure 3)

Differences in hormone levels at 0 and 96 hours between survivors and non-survivors

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On comparing hormone levels at 0 hour, the non-survivors (n=10) had higher mean ADH (24.6 ± 6.9 pg/ml vs. 19.1±6.7 pg/ml; p=0.03), ACTH (51.2±6.4 pg/ml vs. 39.1±7.3; p<0.001) levels, and lower mean cortisol (14.3±7.1 µg/dl vs. 21.2 ± 9.9 µg/dl; p=0.04) levels compared to survivors (n=32). There was no difference in the levels of TSH (p=0.71), FSH (p=0.71) and LH

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(p=0.71) levels between the two groups (Table 3). Five patients in the survivor group and 1 patient in the non-survivor group received etomidate. On performing a sub analysis of patients who did not receive etomidate, there was no difference (p=0.77) in the cortisol level at 0 hours.

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76.2% (32/42) patients had relative adrenal insufficiency and 19%(8/42) patients had severe adrenal insufficiency at 0 hour. The presence of relative and severe adrenal insufficiency in the

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survivors and non-survivors at 0 hour is shown in Table 4. On comparing hormone levels at 96 hours, the non-survivors (n=4) had higher ACTH

(47.4±3.9 pg/ml vs. 29.3±10.5; p=0.002) levels and lower cortisol (6.3±0.6 µg/dl vs. 35.5±11.3 µg/dl; p<0.001) levels. The levels of LH (p=0.60), FSH (p=0.81), TSH (p=0.49) and ADH (p=0.16) did not differ between the survivors and non-survivors.

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DISCUSSION: The endocrinal stress response is an important factor for restoration of homeostasis, and a determinant of outcomes following hemorrhagic shock in trauma patients.3-7 In our study, we

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found that the pituitary hormone levels following hemorrhagic shock vary over 96 hours. The early phase following hemorrhagic shock was marked by high levels of ADH and ACTH. This initial surge gradually declined over the next several days as the hemodynamic status

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normalized. The levels of other pituitary hormones had minimal variation following hemorrhagic shock. Some studies have also described hypothyroidism following hemorrhagic shock. In our

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study however, we did not find any significant changes in TSH levels.15

Trunkey described the tri-modal distribution of death, with hemorrhagic shock being the most common cause of mortality in the early phase of injury.16 The stress response to hemorrhagic shock is a complex interplay of nervous and endocrine systems.3 The endocrinal

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response to hypovolemia involves the activation of the HPA axis and cortisol release. This was seen in our study where we observed a significant increase in the levels of cortisol, the main stress hormone, over 96 hours following hemorrhagic shock. Cortisol enhances the

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catecholamine release, increases the vasogenic responsiveness to catecholamines and maintains microvascular perfusion.8 Because of these roles, it would be reasonable to assume that any

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differences in cortisol levels may be associated with outcomes following hemorrhagic shock. Studies have been done to determine the association of admission cortisol levels on

outcomes in hemorrhagic shock. Stein et al. showed that acute adrenal insufficiency may follow hemorrhagic shock and is strongly associated with mortality.8 In our study, we discovered significant discrepancies in admission cortisol levels, as well as their trends between survivors and non-survivors. The survivors had higher cortisol levels at the time of admission and these

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levels increased significantly over time. However, the non-survivors had lower cortisol levels that further diminished over time. The inadequate cortisol response may originate from disruption of the HPA axis at all three levels i.e. hypothalamic, pituitary or adrenal. The non-

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survivors maintained high levels of ACTH, while the levels of ACTH declined over time in the survivors. This most likely occurred from a negative feedback response of cortisol in the

survivors, which was absent in the non-survivors because of low cortisol levels. These findings

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suggest that the low level of cortisol in non-survivors may be from adrenal hypo responsiveness. Our findings are supported by various anecdotal studies. Hoen et al. demonstrated a subnormal

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adrenal response to corticotropin stimulation in up to 50% trauma patients with ISS more than 16.17 Barton et al. showed decreased responsiveness of the adrenal cortex to ACTH stimulation in severely injured trauma patients.18

The most likely explanation for low cortisol levels following hemorrhagic shock may be

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a decreased blood flow to the adrenal glands. Animal studies have shown decrease in corticosteroid production following hemorrhagic shock.19,20 However, this alone would not explain the sustained decline of cortisol over 96 hours in the non-survivors; as hemodynamic

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status is restored within the first few hours in trauma patients. Higher posttraumatic inflammatory responses from prolonged hemorrhagic shock in the non-survivors may be

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responsible for this. 17,21,22 IL-6 causes sustained release of corticotropin (ACTH). Persistently elevated levels of coricotropin(ACTH) are followed by a blunted response leading to low cortisol levels.23 The finding of sustained high levels of ACTH for 24 hours followed by a progressive decline in the survivors is in coherence with the study of Brizio Molteni et al. who found similar trends in burn patients.24

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The incidence of adrenal insufficiency in critically ill patients varies from 0 to 95%, because of difference in the levels of serum cortisol used to define adrenal insufficiency.25 Over 75% of our study population had relative and 19% of our population had severe adrenal

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insufficiency at the time of presentation. However, they were very similarly distributed between the survivors and non-survivors. In addition, we explored differences in absolute values and the trends of cortisol levels over time between the survivors and non-survivors. The difference in

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cortisol levels and their trends may not be the cause for the difference in mortality, but rather a marker for worse outcomes. Corticosteroids have shown to reduce mortality in hemorrhagic

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shock, vasopressor needs, and systemic inflammatory response syndrome.8 Based on our study, we do not propose corticosteroid administration in patients with worsening trends in cortisol levels. However, we do highlight a possible avenue for intervention that requires further investigation.

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Our study has several limitations including a small sample size. We do not have a control group to compare the changes in hormones to a similar cohort of individuals without hemorrhagic shock. However, there were relative differences in the ACTH and cortisol levels

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and their trends between the survivors and non-survivors. Mean hormone levels at 96 hours in the non-survivor group were based only on 4 patients who survived till this time point. We relied

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on single daily blood draws to determine mean hormone levels for the day. Hormone levels were assessed at the time of arrival (0 hour), which varied for all patients and then every morning as a part of routine blood draws; hence the effects of diurnal variation in hormone levels could not be completely controlled for. Studies have shown disruptions in circadian rhythm for cortisol lasting for several days in burn patients.18 Therefore, it is very unlikely to affect the results of our study. We did not assess the use of pressor agents and its association with cortisol levels

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CONCLUSION: Acute hypopituitarism does not occur in trauma patients with acute hemorrhagic shock. In

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patients who died there was a decrease in cortisol levels, which appears to be adrenal in origin.

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Daniel PM, Prichard MM, Treip CS. Traumatic infarction of the anterior lobe of the

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All, n = 42

Survivors, n = 32

Non-survivors, n = 10

p Value

Age, y, mean ± SD

36 ± 12

37 ± 11

35 ± 12

0.63

> 65 y, n (%)

4 (9.5)

2 (6.25)

2 (20)

0.49

Male, n (%)

34 (81)

27 (84.3)

7 (70)

0.58

38 (90.5)

30 (93.75)

8 (80)

0.49

85.4 ± 64.5

89.6 ± 58.2

71.9 ± 72.8

0.43

4 (9.5))

1 (3.1)

3 (30)

0.01*

95 ± 34.7

93.6 ± 37.2

99.2 ± 35.7

0.68

HR ≥ 120/min, n (%)

9 (21.4)

5 (15.6)

4 (40)

0.23

Admission temperature, mean ± SD

37 ± 0.7

37.2 ± 0.5

36.4 ± 0.7

<0.001*

GCS, median, [IQR]

15 [14-15]

15 [14-15]

15 [14-15]

0.81

Injury severity parameters

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Table 1. Demographics

4 (9.5)

3 (9.4)

1 (10)

0.91

17 (40.5)

13 (40.6)

4 (40)

0.97

12 (28.6)

8 (25)

4 (40)

0.61

9 (21.4)

8 (25)

1 (10)

0.57

ISS, median [IQR]

26 [18-38]

26 [17-38]

26 [19-39]

0.65

ISS>24, n (%)

32 (76.2)

25 (78.1)

7 (70)

0.92

Variables

Vital parameters

Fall MVC Gun shot

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Stab wound

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Mechanism of injury, n (%)

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Admission SBP, mean ± SD Non-recordable SBP on admission, n (%) Admission HR, mean + SD

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Whites, n (%)

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Demographics

*Significant, p<0.05.

SD, standard deviation; IQR, interquartile range; SBP, systolic blood pressure; HR, heart rate; GCS, Glasgow coma scale; MVC, motor vehicle collision; ISS, injury severity score.

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Table 2. Initial Management Survivors, n = 32

Non-survivors, n = 10

p Value

5 (11.9)

4 (12.5)

1 (10)

0.8

Hgb, mg/dL, mean ± SD

12.6 ± 5.2

12.8 ± 5.6

≤ 8 mg/dL, % (n)

11 (26.2)

8 (25)

153.4 ± 49.7

≤ 100x103, n (%)

Etomidate administration, n (%) Laboratory parameters

0.72

3 (30)

0.75

149.93 ± 59.1

164.59 ± 45.3

0.48

7 (16.67)

5 (15.6)

2 (20)

0.75

INR, mean ± SD

1.5± 1.2

1.3 ± 0.9

2±1

0.04*

INR ≥ 1.5, n (%)

22 (52.4)

13 (40.6)

9 (90)

0.02*

Blood lactate, mean ± SD

8.5± 2.9

8.1 ± 1.6

9.8 ± 2.7

0.02*

Base deficit ≥ 1.5, n (%)

17 (40.5)

10 (31.2)

7 (70)

0.04*

PRBC, units, mean ± SD

7.7 ± 4.9

7.5 ± 4.7

8.2 ± 5.3

0.69

FFP, units, mean ± SD

7.5 ± 4.1

7.4 ± 4.0

7.9 ± 4.8

0.76

Massive transfusion, n (%)†

20 (51.8)

14 (43.7)

6 (60)

0.59

Surgical intervention, n (%)

34 (81)

26 (83.2)

8 (80)

0.93

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Blood transfusion in first 24 h

*Significant, p<0.05.

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12.1 ± 4.3

Platelet count, mean ± SD

Massive transfusion was defined as more than 10 U of packed red blood cell transfusion in the first

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†

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All, n = 42

Variables

24 h after arrival in the emergency department.

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Hgb, hemoglobin; SD, standard deviation; INR, international normalized ratio; PRBC, packed red blood cells; FFP, fresh frozen plasma..

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Table 3. Admission Level of Hormones All, n = 42, mean ± SD

Survivors, n = 32, mean ± SD

Non-survivors, n = 10, mean ± SD

p Value

0-60

42 ± 8.7

39.1 ± 7.3

51.2 ± 6.4

<0.001*

ADH, pg/mL

1.0-13.3

20.4 ± 7.1

19.1 ± 6.7

24.6 ± 6.9

0.03*

TSH, µIU/mL

0.49-4.67

1.46 ± 0.6

1.44 ± 0.6

1.51 ± 0.5

0.71

FSH, mIU /mL

0.8-22.9

9.2 ± 3.0

9.3 ± 3.1

8.9 ± 2.1

0.71

LH, mIU /mL

0.2-20

11.0 ± 5.2

11.2 ± 5.9

10.5 ± 2.6

0.71

5.6-21.3

19.6 ± 9.7

21.2 ± 9.9

14.3 ± 7.1

0.04*

ACTH, pg/mL,

M AN U

Cortisol, µg/dL

SC

Hormones

RI PT

Reference range

*Significant, p<0.05.

ACTH, adrenocorticotropin hormone; ADH, anti-diuretic hormone; TSH, thyroid stimulating

AC C

EP

TE D

hormone; FSH, follicle stimulating hormone; LH; leutinizing hormone.

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Table 4. Acute Adrenal Insufficiency Variables

Total population (n=42)

Survivors (n=32)

Non-survivors (n=10)

RI PT

Relative adrenal 32 (76.2) 24 (75) 8 (80) insufficiency, n (%) Severe adrenal 8 (19) 6 (18.7) 2 (20) insufficiency, n (%) Relative adrenal insufficiency defined as cortisol level <25 µg/dL; severe adrenal insufficiency

AC C

EP

TE D

M AN U

SC

defined as cortisol level <10 µg/dL.

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Figure Legends Figure 1. Variation in hormone levels of the entire population over 96-hours. *p Value <0.05

RI PT

for change in hormone levels from 0 to 96 hours.

in hormone levels from 0 to 96 hours.

SC

Figure 2. Variation in hormone levels of survivors over 96-hours. *p Value <0.05 for change

Figure 3. Variation in hormone levels of non-survivors over 96-hours. *p Value <0.05 for

AC C

EP

TE D

M AN U

change in hormone levels from 0 to 96 hours.

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Précis Pituitary insufficiency does not seem to occur after hemorrhagic shock in trauma patients. Admission cortisol levels were significantly lower in non-survivors as compared to survivors,

AC C

EP

TE D

M AN U

SC

RI PT

which further trended down over time. The source of low cortisol appears to be adrenal.

20

M AN U

SC

RI PT

Mean Hormone Levels

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AC C

EP

TE D

Variations Over Time

SC M AN U TE D EP AC C

Mean Hormone Levels

RI PT

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Variations Over Time

EP

TE D

M AN U

SC

Mean Hormone Levels

RI PT

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AC C

Variations Over Time