8th Edition APGO Objectives for Medical Students

8th Edition APGO Objectives for Medical Students Amenorrhea

Rationale The absence of normal menstrual bleeding may represent an anatomic or endocrine problem. A systematic approach to the evaluation of amenorrhea will aid in the diagnosis and treatment of its cause.

Objectives: The student will be able to list: • Definitions of primary amenorrhea, secondary amenorrhea and oligomenorrhea • Causes of amenorrhea • Evaluation methods • Treatment options

Primary: No menses by age 14 yr. in the absence of growth or development of secondary sexual characteristics No menses by age 16 yr. regardless of the presence of normal growth and development with appearance of secondary sexual characteristics Secondary: In a woman who has been menstruating, absence of menstruation for a length of time equivalent to a total of at least 3 of the previous cycle intervals, or 6 months of amenorrhea Oligomenorrhea: menses at intervals >35 days Normal menstrual cycle Definitions

Causes Anything that interferes with normal sequence which culminates in menstruation, i.e. disorders of the CNS (hypothalamus), anterior pituitary, ovary, uterus or outflow tract

Causes - Pregnancy • most frequent cause of amenorrhea

(hypogonadotropic hypogonadism) Suppression of GnRH pulsatile secretion - second most frequent cause This causes low FSH and LH and, therefore, also a low estrogen level and no withdrawal bleeding following progesterone challenge Stress - corticotropin-releasing hormone (CRH) directly inhibits hypothalamic GnRH secretion (probably by augmenting endogenous opioid secretion) Weight loss - especially anorexia Excess exercise related both to percent body fat and energy expenditure Severe emotional stress Chronic disease Kallmann’s syndrome Amenorrhea with anosmia Caused by mutation of short arm of X chromosome that encodes a protein responsible for functions necessary for neuronal migration Cells that produce GnRH originate in olfactory area and migrate during embryogenesis along cranial nerves that connect nose and forebrain Effects 5 to 7 times more males than females May be X-linked, autosomal dominant, or autosomal recessive CNS tumor - hamartomas Other - sarcoidosis Causes - Hypothalamic dysfunction

hypogonadotropic, hypogonadism, i.e. low FSH, LH and estrogen levels Pituitary adenomas (benign adenomas of lactotrophs) Produce prolactin, elevated levels inhibit pulsatile secretion of GnRH Common Found in 1/3% of women with secondary amenorrhea Only 1/3 of women with high prolactin levels have galactorrhea Almost never malignant (only 40 cases of primary pituitary cancer in the world literature through 1989) If large (>1 cm,referred to as macroadenoma): May compress optic chiasm causing bitemporal hemianopsia and/or headaches Diagnosed via imaging studies (MRI or CT) in patients with elevated prolactin level Treatment Surgical - rarely used as complete cure rate is low and recurrence common Medical - dopamine agonists (bromocriptine or cabergoline) - remember, inhibit pituitary prolactin secretion Surveillance - many microadenomas (<10mm) regress spontaneously or remain small. Note: this does not treat patientﾕs hypoestrogenic status Causes - Pituitary Dysfunction

Causes - Pituitary Dysfunction Hyperthyroidsm • Elevated thyrotropin-releasing hormone levels stimulate pituitary cells that secrete prolactin. • In addition, thought to be associated with declining hypothalamic content of dopamine and, therefore, a removal of dopaminergic suppression of prolactin secretion.

Causes - Pituitary Dysfunction Lesions compressing the pituitary stalk causing interference with delivery of hypothalamic GnRH (all rare compared to pituitary adenomas) • Other pituitary tumors - craniopharyngiomas, meningiomas, gliomas, metastatic tumors, chordomas • May also cause optic chiasm compression even when small • Non-neoplastic intrasellar - gummas, tuberculomas, fat deposits • Lesions near the pituitary- internal carotid artery aneurysms, obstruction of the aqueduct of Sylvius

Causes - Pituitary Dysfunction Empty sella syndrome • Congenital incompleteness of sellar diaphragm that allows an extension of subarachnoid space into the pituitary fossa • Found in 5% of autopsies, 85% are women, incidence of 4-16% in patients who present with amenorrhea/ galactorrhea 2

Causes - Pituitary Dysfunction Pituitary infarction - Sheehan’s syndrome • Acute necrosis of pituitary gland due to postpartum hemorrhage, with hypotension, decreased perfusion and shock • Symptoms of panhypopituitarism seen early in the postpartum period, especially failure of lactation and loss of pubic and axillary hair • Is life threatening • Exceedingly rare in U.S.

Causes - Pituitary Dysfunction Lactation (physiologic hyperprolactinemia)

Premature ovarian failure (hypergonadotropic hypogonadism) - elevated FSH and LH Defined as ovarian failure at age <40 yr. Due to early depletion of ovarian follicles normal karyotype is also linked to neurosensory deafness (Perrault syndrome) Etiologies Autoimmune - need to evaluate for other autoimmune disorders, especially thyroid, adrenal Infection - such as mumps oophoritis Irradiation or chemotherapy Castration Gonadal dysgenesis Most common cause of primary amenorrhea Karyotype if age <30 yr. May be abnormal karyotype (45, X; or mosaics) or may be normal If Y chromosome present, even in mosaic, gonads need to be removed to prevent tumor formation or virilization Gonadal dysgenesis associated with Causes - Premature Ovarian Failure

Causes - Chronic Anovulation Chronic anovulation due to increased androgens • Cushing’s syndrome • Congenital adrenal hyperplasia • Polycystic ovarian syndrome

Disorders of the uterus or outflow tract - normal FSH, LH and prolactin; no withdrawal with progesterone challenge Müllerian anomalies Discontinuity by segmental disruptions of the Müllerian tube, i.e. obliteration of vaginal orifice, complete transverse vaginal septa, absence of a cervix, imperforate hymen Absence of uterus in normal (46, XX) female - Mayer- Rokinatsky-Kuster-Hauser syndrome 2nd most common cause of primary amenorrhea Müllerian development with congenital absence of uterus and/or vagina Müllerian anomalies frequently associated with urinary tract anomalies, including ectopic kidney, renal agenesis, horseshoe kidney, and abnormal collecting ducts (remember, genital and urinary systems develop in close proximity and timing during embryogenesis.) May also be associated with skeletal anomalies Causes - Disorders of Uterus

Causes - Absence of Uterus Absence of uterus in a phenotypic female but genotypic male (46, XY) - called testicular feminization - androgen insensitivity

Causes - Absence of Uterus • Male pseudohermaphrodite • 3rd most common cause of primary amenorrhea • X-linked recessive disorder of the gene responsible for the androgen intracellular receptor; therefore, despite normal male levels of testosterone, there is a lack of testosterone action • Patients appear normal female at birth except for possible presence of inguinal hernias. Growth and development are normal, except tend to be eunuchoid (long arms, big hands and feet) and tall. (May commonly become actresses!) Breasts are large with scant glandular tissue. Uteri absent, and vagina is blind canal and usually short. Testes abdominal or in an inguinal hernia • This is the one exception to removing X, Y gonads in a phenotypic female as soon as diagnosed. These patients should have gonads removed after puberty, as it allows for more normal development of puberty, and testicular tumors in these patients have not been encountered prior to puberty

Causes - Endometrial atrophy Endometrial atrophy secondary to prolonged progesterone administration • Depo-Provera • Oral contraceptives • Norplant

Asherman’s syndrome - endometrial scarring Generally result of overzealous postpartum curettage, but may also be after other uterine surgery Diagnosed with hysterosalpingogram, sonohysterogram or hysteroscopy Generally will not have a withdrawal bleed from Provera May also present with multiple miscarriages, dysmenorrhea, hypomenorrhea or infertility Treated by hysteroscopic lysis of adhesions Infection Tuberculosis - common cause of amenorrhea in undeveloped countries Schistosomiasis IUD related infection or severe PID Causes - Endometrial Damage

Treatment A. Treat the cause, i.e. hypothyroidism, pituitary adenoma, infection, stress, outflow tract scarring or obstruction, etc.

Treatment B. If anovulatory, need to give periodic progesterone to prevent endometrial hyperplasia • Desires conception - ovulation induction (progesterone in pregnancy will, in essence, prevent hyperplasia, as will the pregnancy itself) • Not desiring pregnancy at this time • Oral contraceptives • Cyclic progestins

Treatment C. Hypoestrogenic anovulation - need to induce estrogen production or give estrogen to prevent bone loss. Then need to make sure patient also has progesterone so they donﾕt have “unopposed estrogen”causing endometrial hyperplasia or carcinoma: • Gonadotropins - typically used only for fertility • Pulsatile GnRH - typically used only for fertility • Oral contraceptives ･HRT

Frequent sources of confusion Post-pill amenorrhea should be evaluated same as any other amenorrhea if has been 6 mo. since discontinuing OCPs or 12 mo. since last injection of Depo- Provera

Frequent sources of confusion Is it medically necessary for a woman to have a period once a month?No, but estrogen is necessary to build and maintain bone mass, decrease risk of cardiovascular disease, etc. Estrogen alone (unopposed estrogen) significantly increases risk of endometrial hyperplasia and adenocarcinoma. Progesterone counteracts these risks. The combination of estrogen and cyclic progesterone will produce a bleeding cycle. The two hormones given together continuously (ex., taking oral contraceptives without taking the placebo week) creates amenorrhea without the adverse risks discussed above

Frequent sources of confusion If a woman is not menstruating, where does all that blood go? (A question often asked by patients, friends and family) - depends on the cause of amenorrhea. For example: if imperforate hymen is cause, a hematometrium may develop along with severe endometriosis. In the case of continuous use of OCPs or Depo-Provera, the endometrium is atrophic so cannot “build up”

Frequent sources of confusion If a woman is amenorrheic and doesn’t want to have periods, should she be evaluated?Be treated? Yes, to rule out disease processes and evaluate for bone loss depending on length of time she was amenorrheic. She may still be able to be amenorrheic - for instance, if treated with continuous OCPs.

Frequent sources of confusion Can a woman who is amenorrheic become pregnant?Yes, depending on the cause of amenorrhea

References • Speroff L et al. Clinical Gynecologic Endocrinology and Infertility, 6th ed. Williams and Wilkens: Baltimore, MD, 2000. • Adapted from Association of Professors of Gynecology and Obstetrics Medical Student Educational Objectives, 7th edition, copyright 1997

Clinical Case Amenorrhea

Patient Presentation A 26-year-old G2P2 woman with LMP= 6 months ago presents with a concern regarding no periods. She delivered two full term healthy children vaginally and their ages are 5 and 3. She stopped breastfeeding 2 years ago. She has noted a persistent breast discharge, but no breast masses. She is not using any contraception, but parenting has taken a toll on the husband-wife relationship and they infrequently find the opportunity to have intercourse.

Ob-gyn history G2 P2. 2 full-term vaginal deliveries of a 6-0 pound girl and a 7-8-pound boy. Pap smears are up-to-date and normal. No STDs. Past medical history Postpartum depression, which resolved after one year on an SSRI. Past surgical history Cholecystectomy after her first pregnancy Social history Nonsmoker. Occasional alcohol. No street drugs. Married. Works as a housewife. Family history Noncontributory. Patient Presentation

Patient Presentation ROS • Increased stress since the delivery of the second child. Occasional hot flashes. Fatigue. Headaches. Difficulty losing the pregnancy weight gain. Physical exam • VS: BP= 120/80, P= 64, R= 18, Ht= 5’8”, Wt= 160 poundsGeneral: tired appearing Caucasian woman in no apparent distress

Patient Presentation HEENT: NC/AT • Neck: No thyromegaly palpable • Lungs: clear • CV: Regular rate, no murmurs • Breasts: bilateral milky white discharge with expression. No masses, dimpling or retraction • Abdomen: non-tender, no distension, no masses, no hepatosplenomegaly • Ext: Non-tender, no edema, DTRs 1+/= bilaterally • Pelvic exam: Normal external genitalia, moist vagina with decreased rugae, no discharge, Cervix is multipara, non-tender, and no lesions, uterus is non-tender, mobile and normal size, adnexae are non-tender and no palpable masses • Allergies: None • Medications: Multi-vitamin

Patient Presentation Laboratory/studies: • HCG= negative • FSH= 3.5 mIU/mL • TSH= 2.5 uIU/mL • Prolactin= 130 ng/mL; repeat on fasting, 100ng/mL • Breast discharge smear reveals multiple fat droplets • MRI of the head reveals a 0.8 cm mass in the anterior pituitary Diagnoses • Amenorrhea • Galactorrhea • Prolactinoma (Pituitary microadenoma)

Treatment This patient was treated with Cabergoline (a dopamine agonist) on a weekly basis and the dose was increased until her prolactin level was in the normal range. She tolerated the medication well. She had return of menses within a few months time. Her galactorrhea slowly resolved. She is now being followed on an annual basis.

Teaching Points • There are multiple causes of amenorrhea and the student should become familiar with them. This patient with her symptomatology could have easily have been pregnant, had hypothyroid disease, premature ovarian failure or hypothalamic amenorrhea associated with stress. It is important to consider the entire differential diagnoses list prior to treatment.

Teaching Points • Prolactinomas are the most frequent pituitary tumor and these microadenomas tend to have an indolent course. • The elevated prolactin levels produce amenorrhea by inhibiting the pulsatile secretion of GnRH and result in low gonadotropins and estrogen levels.

Teaching Points • It is important to also evaluate both the TSH and prolactin levels in these patients. Hypothyroidism may be present with increased prolactin levels since TRH can stimulate both TSH and prolactin secretion. • Only 1/3 of women with high prolactin levels will have galactorrhea.

Questions Amenorrhea

8th Edition APGO Objectives for Medical Students