The Continuous Textbook of Women\'s Medicine Series ISSN: 1756-2228; DOI 10.3843/GLOWM.414493 23/09/2021 This chapter should be cited as follows: Lust K, Tellam J, Glob. libr. women's med., ISSN: 1756-2228; DOI 10.3843/GLOWM.414493 The Continuous Textbook of Women’s Medicine Series – Obstetrics Module Volume 8 MATERNAL MEDICAL HEALTH AND DISORDERS IN PREGNANCY Volume Editor: Clinical Associate Professor Sandra Lowe, University of New South Wales, Australia Chapter Adrenal Disorders in Pregnancy First published: February 2021 AUTHORS Karin Lust, MBBS, FRACP Director Women’s and Newborn Services, General & Obstetric Physician, Royal Brisbane and Women’s Hospital, Herston, Australia Jane Tellam, MBBS Endocrinology and Obstetric Medicine Advanced Trainee, Department of Endocrinology and Obstetric Medicine, Royal Brisbane and Women’s Hospital, Herston, Australia PHYSIOLOGY OF ADRENAL GLAND FUNCTION IN PREGNANCY There are two major components to the adrenal glands: the cortex and medulla. The adrenal cortex consists of the outermost zona glomerulosa (ZG) which produces mineralocorticoids (aldosterone), the middle zona fasciculata (ZF) which produces glucocorticoids (cortisol) and the zona reticularis which produces androgens (dehydroepiandrosterone, DHEA, and the sulfated version DHEA-S).1,2 The adrenal medulla produces adrenaline and noradrenaline. Cortisol Cortisol is essential for maintaining blood pressure, electrolyte physiology and glycemic control. Ten to fteen per cent circulates freely in non-pregnant women, with the remainder bound to cortisol binding globulin (CBG) and albumin.3 Both free and bound cortisol are elevated throughout pregnancy and spike at delivery. By the third trimester, cortisol levels have increased by 2–3 fold. Diurnal variation is preserved, characterized by high levels of cortisol in the morning and low levels at night.4 Multiple mechanisms are involved (Figure 1):5 1. The placenta is a secondary site for production of adrenocorticotropic hormone (ACTH), corticotropin releasing hormone (CRH) and cortisol. 2. Usual negative feedback loops are altered. Unlike hypothalamic CRH, placental CRH increases with cortisol (positive feedback loop) leading to further increases in both CRH and cortisol. 3. Raised estrogen levels in pregnancy increase corticosteroid binding globulin (CBG). This causes an increase in total cortisol and a reduction in cortisol clearance. The half-life of cortisol is doubled. Raised progesterone levels in pregnancy displace cortisol from CBG, further elevating free cortisol. 4. Obstetrics - V8 - Maternal medical health and disorders in pregnancy - Chapter - Adrenal Disorders in Pregnancy Page 1 of 18 The Continuous Textbook of Women\'s Medicine Series ISSN: 1756-2228; DOI 10.3843/GLOWM.414493 23/09/2021 5. Fetal hypothalamic-pituitary-adrenal (HPA) axis activity begins at approximately 20 weeks' gestation. 6 Cortisol can cross the placenta bi-directionally (mother to fetus, and fetus to mother) and is regulated by placental 11-βhydroxysteroid dehydrogenase type 2 (11-βHSD type 2).3,4 Excess maternal steroid exposure has been linked to transient fetal HPA axis suppression, low birth weight, metabolic dysfunction and behavioral alterations in offspring.6 Figure 1 Hypothalamic-pituitary-adrenal (HPA) axis in pregnancy. Solid arrows indicate positive feedback and dashed arrows indicate negative feedback. CRH, corticotropin releasing hormone; ACTH, adrenocorticotropic hormone; CBG, corticosteroid binding globulin.5 Renin-angiotensin-aldosterone system (RAAS) Aldosterone controls salt and water balance in the kidney. Its net eect is sodium retention with resultant water reabsorption to maintain blood pressure. It has a complex regulatory system detailed in Figure 2. Figure 2 Renin-angiotensin-aldosterone system (RAAS) in pregnancy. Solid black arrows indicate positive feedback and dashed black arrows indicate negative feedback. ACE, angiotensin-converting enzyme.5 Upregulation of the RAAS system also occurs in pregnancy. Plasma renin activity (PRA) elevates in early pregnancy and reaches 3–7 fold by the third trimester. This is accompanied by receptor based refractoriness to the eects of angiotensin and hence blood pressure does not rise. Aldosterone follows a similar pattern, peaking at 38 weeks at 5–20 fold. There is ongoing aldosterone responsiveness to usual stimuli (for example posture, blood volume, dietary salt). Progesterone is an aldosterone antagonist and plays a role in regulation of aldosterone activity.5 Dehydroepiandrosterone/dehydroepiandrosterone sulfate (DHEA/DHEA-S) Obstetrics - V8 - Maternal medical health and disorders in pregnancy - Chapter - Adrenal Disorders in Pregnancy Page 2 of 18 The Continuous Textbook of Women\'s Medicine Series ISSN: 1756-2228; DOI 10.3843/GLOWM.414493 23/09/2021 There is increased androgen secretion by the adrenal cortex in pregnancy. Placental aromatase metabolizes these to estradiol and estrone.7 Although there is greater production of androgens, overall the levels decrease due to the aromatization process. Adrenaline/noradrenaline Adrenaline and noradrenaline are essential for maintaining homeostasis in multiple systems, particularly the cardiovascular system. Metabolites known as metanephrines are measured to assess for states of adrenaline/noradrenaline excess and are unchanged in pregnancy.8 ADRENAL INSUFFICIENCY Adrenal insuciency (AI) is relatively rare in pregnancy and the exact prevalence of AI in pregnancy is unknown. AI can be divided into primary, secondary or tertiary causes (Table 1).9,10 In primary adrenal insuciency there is elevated adrenocorticotropic hormone (ACTH) and destruction of the adrenal cortical gland function leading to glucocorticoid, adrenocorticoid and mineralocorticoid deciency. Secondary AI is due to lack of ACTH stimulation and tertiary is due to a lack of corticotropin releasing hormone (CRH) stimulation. In developed countries autoimmune adrenalitis (Addison’s disease) is the most common cause of primary AI, whereas in developing countries tuberculosis destruction of the adrenal gland is more common. The prevalence of primary AI in developed countries is reported to be 96–140 per one million population.11,12 Exogenous corticosteroids for the treatment of other systemic diseases (>5 mg/day prednisone or equivalent doses of other corticosteroids for longer than 3 weeks in the past year) increases the risk of AI.10 A recent systematic review of glucocorticoid therapy and subsequent AI in adults demonstrated that AI was present at <0.5 mg prednisolone equivalent dose/day, <4 weeks of exposure, cumulative dose <0.5 g, and following tapered withdrawal of glucocorticoids. The authors advised that clinicians should be vigilant for AI with all degrees of glucocorticoid exposure.13 The ingestion of corticosteroids can lead to ACTH and CRH suppression resulting in adrenal atrophy. AI was previously associated with increased maternal and fetal morbidity and mortality. Modern glucocorticoid and mineralocorticoid replacement therapy along with improvements in obstetric and neonatal care ensures that the majority of women can expect good maternal and fetal outcomes.9,10 Table 1 Causes of adrenal insuciency (AI).9,10 Adrenal insuciency type Pathophysiology Medical disorders Primary Loss of adrenal cortical gland • Autoimmune adrenalitis (Addison’s disease) alone or part of function autoimmune polyglandular syndrome (type 1, 2, 4) • Bilateral adrenal hemorrhage • Infiltration by infectious process, e.g. tuberculosis or fungal • Infiltration by neoplasms • Adrenal infarction • Inborn errors of metabolism • Enzyme deficiency resulting in complete or non-classical congenital adrenal hyperplasia (CAH) Secondary Dysfunction of pituitary gland • Pituitary tumors or surgery with ACTH deciency • Lymphocytic hypophysitis • Sheehan’s syndrome • Suppression of hypothalamic pituitary adrenal axis (HPA) by high dose exogenous glucocorticoid administration* Obstetrics - V8 - Maternal medical health and disorders in pregnancy -• CShuaptper e- sAsdiroenn aol fD HisPorAd earxs iisn bPyre hgingahn cdyose exogenous glucocoPratigceo 3id of 18 The Continuous Textbook of Women\'s Medicine Series ISSN: 1756-2228; DOI 10.3843/GLOWM.414493 23/09/2021 Tertiary Dysfunction of hypothalamus • Suppression of HPA axis by high dose exogenous glucocorticoid Adrenal with CRH deciency * insuciency administration type Pathophysiology Medical disorders *Combined secondary and tertiary AI. Clinical features AI is usually diagnosed prior to pregnancy; a recent review reporting only 17.7% of cases being diagnosed in pregnancy with equal distribution in all three trimesters.9 Symptoms of AI are nonspecic and can mimic normal physiological symptoms of pregnancy such as fatigue, low blood pressure, nausea, vomiting and linea nigra. AI should be considered in women presenting with excessive fatigue, weight loss, malaise, vomiting, dizziness, hyperpigmentation, abdominal pain, salt craving and or electrolyte disturbance. Symptoms may worsen across the day. Pigmentation from Addison’s involves nonexposed parts of the skin, creases of hands, extensor surfaces, mucous membranes and in scars. Laboratory ndings in primary AI may include hyponatremia, hyperkalemia, mild anemia and metabolic acidosis. Hypoglycemia and hypercalcemia may occur in an adrenal crisis. A prior personal or family history of autoimmune disease should raise the clinical suspicion of AI in a woman presenting with symptoms.9,10 Adrenal crises can be associated with hyperemesis gravidarum, infections,