Neuroendocrine Disorders in Women

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1 Neuroendocrine Disorders in Women Ursula B. Kaiser, M.D. Chief, Division of Endocrinology, Diabetes and Hypertension Brigham and Women s Hospital Professor of Medicine, Harvard Medical School

2 Case Presentation 22 year old woman presents for assessment of irregular menses Menarche age 13 Since age 18, menses every 3-6 months. Now amenorrheic for one year. No medications No hirsutism or acne, no galactorrhea, no hot flashes Denies weight loss, stress, excessive exercise BMI 21.5% No hirsutism, no galactorrhea PRL ng/ml (normal < 23.3) Androgens, TFTs, FSH, other pituitary function all normal Pituitary MRI 2-3 mm microadenoma What is the cause of her amenorrhea? What would you do?

3 Secondary Amenorrhea Definitions Secondary amenorrhea: Ø absence of menses for more than 3 months in a regularly cycling woman Ø or more than 6 months in women with irregular cycles. Oligomenorrhea: Ø cycle length > 35 days Ø or fewer than 9 menstrual cycles per year

4 Secondary Amenorrhea: What could be the cause? Causes*: Ø Hypothalamic: Functional hypothalamic amenorrhea (35%) Ø Pituitary: Hyperprolactinemia (20%) Ø Ovarian: Polycystic ovary syndrome (30%) Ø Ovarian: Premature ovarian failure (10%) Ø Other * after exclusion of pregnancy

5 Hyperprolactinemia: First, what does prolactin do? q Member of hormone family that includes GH and hpl q Produced in lactotropes, widely distributed throughout the anterior pituitary q Lactation q Suppression of hypothalamic-pituitary-gonadal axis q Receptors in breast, liver, ovary, testis, and prostate q Other functions? Immune effects? Role in men?

6 Physiology Of Prolactin Secretion q Pulsatile pulses/day q Peak levels during sleep q Stimulated by meals (protein) q Varies during menstrual cycle Clin Endocrinol 5:643,1976

7 Regulation Of Prolactin Secretion DA _ TRH + Hypothalamus Estrogen + + PRL Pituitary Spinal afferent Pathways (e.g., suckling) Breast

8 Causes of Hyperprolactinemia Physiologic: q Sleep q Food (protein) q Ovulatory and luteal phases q Stress Ø physical exertion Ø surgery Ø insulin hypoglycemia Ø seizures q Sexual intercourse q Nipple stimulation q Estrogen q Pregnancy Am J Obstet Gynecol 129:454,1977

9 Causes Of Hyperprolactinemia Pharmacologic: q Dopamine receptor antagonists Ø phenothiazines Ø antipsychotics - haloperidol, risperidone Ø metoclopromide, domperidone q Dopamine depleting agents Ø reserpine Ø alpha-methyldopa q Tricyclic antidepressants q SSRIs q Calcium channel blockers - verapamil q H2 antagonists - cimetidine q Angiotensin converting enzyme inhibitors - enalapril q Opiates, cocaine q Protease inhibitors q Estrogens

10 Causes of Hyperprolactinemia Pathophysiologic/ Other : q Neurogenic Ø Chest wall trauma Ø Spinal cord lesions Ø Herpes zoster q Primary hypothyroidism q Chronic renal disease q Liver disease q Germline PRLR loss-of-function mutation q Idiopathic hyperprolactinemia Spinal afferent Pathways (e.g., suckling) Estrogen + TRH DA _ + PRL +

11 Causes of Hyperprolactinemia Hypothalamic Disorders: q Tumors q Infiltrative diseases q Pituitary stalk interruption q Pseudotumor cerebri q Cranial irradiation Estrogen + TRH DA _ + PRL + Spinal afferent Pathways (e.g., suckling)

12 Causes of Hyperprolactinemia Pituitary disorders: q Prolactinoma q Acromegaly q Other pituitary tumors ØNonfunctioning adenoma ØMeningioma q Pituitary stalk section q Empty sella syndrome q Infiltrative diseases Idiopathic Spinal afferent Pathways (e.g., suckling) Estrogen + TRH DA _ + PRL +

13 Approach To Hyperprolactinemia q Diagnosis single measurement serum prolactin q Assess for symptoms and signs of hyperprolactinemia q If borderline, verify prolactin level in nonstimulated state q Assess for physiologic, pharmacologic, and other pathophysiologic causes Ø Pregnancy test Ø TSH Ø BUN, creatinine Melmed et al. JCEM 2011 (Endo Soc Guidelines)

14 When Should You Do An MRI? When an elevated serum prolactin level is not associated with a clear secondary cause, a pituitary MRI scan should be performed to evaluate for the presence of a prolactinoma or other lesion, and to distinguish micro- from macroprolactinomas.

15 What If the Prolactin and the Symptoms Are Discordant? 1. If the prolactin is high but the patient is asymptomatic: Macroprolactin 2. If the prolactin is mildly elevated in the presence of a large pituitary tumor: Hook effect Gibney et al. JCEM 2005 Petakov et al. J Endocrinol Invest 1998

16 Potential Sources of Interference in Immunoradiometric Assays for Prolactin Hook Effect Smith TP et al. Nat Clin Pract Endocrinol Metab 3: , 2007

17 Management Of Hyperprolactinemia Objectives of Therapy: q Restore prolactin levels to normal with return of eugonadal state q Reduce tumor size q Preserve pituitary function q Prevent disease recurrence and progression

18 Therapeutic Options: q medical therapy with a dopamine agonist Ø bromocriptine Ø cabergoline (D2R agonist) q surgery q observation q withdrawal of putative causative agent q estrogen/testosterone replacement q radiation q pregnancy Management Of Hyperprolactinemia

19 Regulation Of Prolactin Secretion + DA _ TRH + Estrogen + + PRL - Dopamine agonists Neurogenic pathways

20 Comparative Efficacy Of Bromocriptine And Cabergoline Webster et al. NEJM 331:904,1994

21 Prolactinoma In Pregnancy q Significant tumor enlargement in 1-2% of microadenomas q Significant tumor enlargement in 15-35% of macroadenomas q Approach: discontinue dopamine agonist, monitor patients with microadenomas by symptoms only q Approach: monitor patients with macroadenomas at baseline and in each trimester (or each month) clinically and with visual field testing q If tumor enlargement occurs, initiate bromocriptine therapy q Surgical resection is an alternative

22 Bromocriptine in Pregnancy q > 6000 pregnancies - no increase in multiple pregnancies, miscarriage, ectopic pregnancy, trophoblastic disease, or congenital malformations q No teratogenic or embryotoxic effects in animal studies q Both bromocriptine and cabergoline are pregnancy category B Molitch Endocrinol Metab Clin North Amer 2006 Colao et al. Clinic Endocrinol 2008

23 Back to our Case: What about hypothalamic amenorrhea? Causes*: Ø Hypothalamic: Functional hypothalamic amenorrhea (35%) Ø Pituitary: Hyperprolactinemia (20%) Ø Ovarian: Polycystic ovary syndrome (30%) Ø Ovarian: Premature ovarian failure (10%) Ø Other * after exclusion of pregnancy

24 Back to our Case: What about hypothalamic amenorrhea? Hypothalamus GnRH (+) LH (+) FSH (+) Anterior Pituitary Ovary Sex steroids (+/-) Inhibin (-)

25 The Updated Hypothalamic-Pituitary-Gonadal Axis Energy Balance NKB NK3R Stress Hyperprolactinemia KISS1R Kisspeptin GnRH Cortisol Hypothalamus LH FSH Anterior Pituitary Sex steroids (+/-) Ovary/Testis

26 Is It Cushing s Syndrome? Exclude exogenous glucocorticoid exposure Perform one of the following tests 24-h UFC Overnight Late night salivary (> 2 tests) 1-mg DST cortisol (> 2 tests) *Consider caveats for each test* ANY ABNORMAL RESULT Normal (CS unlikely) *Exclude physiologic causes of hypercortisolism* Consult endocrinologist Nieman L et al. JCEM 2008

27 Confounding Issues in Diagnosis of Cushing s Disease Physiologic Hypercortisolism [Pseudo-Cushing s syndrome] Acute psychological stressors-depression/ psychosis/ocd Alcohol dependence/withdrawal Poorly-controlled diabetes mellitus Severe obesity/?osa Glucocorticoid resistance syndromes (rare) Pregnancy Possible associated clinical features Malnutrition/anorexia nervosa Intense chronic exercise (marathoners) Physical stress (hospitalization, surgery, pain) Unlikely to have associated clinical features

28 *Caveats - DST* Estrogens increase CBG --> false positive O/N DST Low CBG (critical illness, liver disease, nephrotic syndrome) --> false negative DST Drugs that induce CYP3A4 accelerate DEX clearance --> false positive O/N DST Liver, renal failure reduces DEX clearance --> false negative O/N DST *Get DEX level*

29 *Caveats - UFC* High urine volumes (> 5 L) increase UFC Renal insufficiency reduces UFC Proper collection Best test during pregnancy (but can be high in 2 nd - 3 rd trimester) Avoid in adrenal incidentaloma testing (*consider ACTH*)

30 *Caveats Salivary Cortisol* Depression Shift workers Licorice, chewing tobacco, cigarettes, blood contamination Best test for those on anticonvulsants Best test for cyclic Cushing s syndrome

31 Secondary Amenorrhea: Evaluation Negative hcg Positive Pregnancy History and Physical FSH, LH, E2, PRL, TSH, + T, DHEAS, 17OHP High FSH Abnormal TSH High PRL Work-up for PRL Brain MRI Ovarian Failure High Androgens Hypothyroidism Hyperthyroidism Normal/Low FSH, Low E2 Hypothalamic Amenorrhea PCOS Adrenal hyperplasia Cushing s syndrome Ovarian tumor Adrenal tumor Structural Brain MRI Functional

32 Thank You! Questions?

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