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Amenorrhea Yale 0331..

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  • 1. AMENORRHEA Michael Green, MD, MSc Week 9 Learning Objectives: 1. Systematically evaluate a woman presenting with secondary amenorrhea 2. Appreciate that women with hypoestrogenic amenorrhea are at risk for osteoporosis 3. Know that women with hyperandrogenic anovulation (PCOS and other conditions) are at risk for endometrial hyperplasia→ cancer due to unopposed estrogen 4. Perform, appreciate the limitations of, and interpret the progestin challenge test CASE ONE: A 19-year-old college student presents to your office with a history of amenorrhea for five months. Prior to this, her periods were regular (30 day cycle), with neither dysmenorrhea nor menorrhagia. She is G0P0 and had menarche at age 12. She is sexually active in a monogamous heterosexual relationship, using a condom for contraception. Of note, she swims for the varsity team and has been training for a national tournament. In addition, she admits to feeling "stressed out" over her course work and has lost 12 pounds over the last several months. Questions: 1. What additional information would you obtain on your initial history and physical? Please explain the importance of each finding. See table 2 in the American Family Physician article. Importantly, one should distinguish between primary amenorrhea (absence of menarche by age 16 with secondary sexual characteristics or by 14 in the absence of secondary sexual characteristics), and secondary amenorrhea (absence of menses for three months with previously normal cycles or nine months in woman with previous oligomenorrhea). 2. What is the most likely cause of her amenorrhea? Overwhelmingly, the most likely cause is functional hypothalamic amenorrhea due to vigorous exercise, weight loss, and psychological stress. All of these stressors, as well as depression and anorexia nervosa, can disrupt the normal GnRH stimulation of the pituitary, leading to decreased gonadotropin (FSH, LH) stimulation of ovarian estrogen production and follicular maturation. Thus, these patients have hypoestrogenic amenorrhea. (Patients with premature ovarian failure also have hypoestrogenic amenorrhea. See bonus question for causes and evaluation of patients with estrogenic amenorrhea.)
  • 2. Because this woman’s particular form of competitive athletics is swimming, we should recognize that a subset of swimmers have a distinct amenorrhea syndrome that is characterized by mild hyperandrogenism and normal estradiol levels (Constantini, 1995). Investigators believe that, unlike long distance runners and dancers, swimmers do not need to be thin because swimming is not a weight bearing activity. They recommend that the distinction can be made based on hormonal profiles, weight, and somatotype. Women with this syndrome would then not be at risk for osteoporosis (see question 5). With her weight loss and additional stressors, the swimmer in this case probably has functional hypothalamic amenorrhea. 3. Despite your strong diagnostic suspicion, what minimum initial laboratory evaluation would you order? HCG, TSH, FSH, and prolactin. With few exceptions, pregnancy, thyroid disease, premature ovarian failure, and hyperprolactinemia should be excluded in all cases of amenorrhea. It is also important to recognize that hypothyroidism can cause pituitary gland enlargement and hyperprolactinemia (because the lactrotroph cells cross respond to TSH) and thus should not be confused with a lactotroph adenoma. 4. Her initial laboratory screen is unrevealing. Does she have estrogenic or hypoestrogenic amenorrhea? How would you confirm her estrogen status? Describe the progestin withdrawal test. Will this patient have withdrawal bleeding in response? As above, amenorrhea due to exercise, weight loss or psychological stress is hypoestrogenic, due to inadequate gonadotrophic stimulation of the ovaries. Her estrogen status can be confirmed by the progestin withdrawal test. The patient takes 10 mg of medroxyprogesterone acetate (Provera) p.o. for 10 consecutive days. Any uterine bleeding within two to seven days of stopping the progesterone is considered a "positive test," which establishes both adequate estrogen levels (to proliferate the endometrium) and a competent uterus and outflow tract. In this woman with hypoestrogenic amenorrhea, we would expect no withdrawal bleeding in response to a progestin challenge. Of note, in addition to the ones in the AFP article, there are many different algorithms recommended in the evaluation of amenorrhea. I am not aware of any studies comparing their diagnostic accuracy, efficiency, or cost effectiveness. I think most physicians use them as guides in concert with clinical judgment rather than as binding protocols. Also, other authors discourage the use of the progestin and progesterone-estrogen (see below) challenge tests, citing the chances of false positives (bleeding in patients with low estrogen) and false negatives (no bleeding in patients with normal estrogen) (Practice Committee 2006). They recommend relying strictly on “clinical characteristics and clinical judgment” to differentiate, for example, between hypothalamic amenorrhea and PCOS.
  • 3. 5. She experiences no menstrual bleeding in response to the progesterone challenge. Is this consistent with your leading diagnosis? What other conditions result in this response and how would you exclude them? Her "negative" progestin challenge test most likely confirms her low estrogen state, which is consistent with the diagnosis of functional hypothalamic amenorrhea, strongly suggested by her history. Other causes of hypoestrogenic amenorrhea include infiltrative, neoplastic, or ischemic diseases of the hypothalamus or pituitary and premature gonadal failure (elevated FSH). Given her classic history, however, pursuit of these diagnoses may not be necessary at this point, but we should remember that functional hypothalamic amenorrhea is a diagnosis of exclusion. If this patient did not give such a suggestive history or had CNS symptoms or signs, you would certainly obtain an MRI of the brain. Additionally, instead of inadequate estrogen stimulation of the endometrium, lack of withdrawal bleeding may indicate a nonreactive endometrium or incompetent outflow tract. This can be differentiated by a combined estrogen/progesterone challenge, which corrects a possible estrogen deficiency. However, this step can be safely omitted in a woman with a normal pelvic exam and no history of pelvic infection, trauma, or surgery. On the other hand, if a woman does have a history of, for example, a D & C, and does not have withdrawal bleeding after a combined estrogen/progestin challenge, a hysterosalpingogram or hysteroscopy will probably reveal an anatomic abnormality or abnormal endometrium. 6. Assured that she has a "benign condition," she is not concerned with the temporary absence of her menstrual periods and does not want to get pregnant. Would you acquiesce or insist on initiating treatment? For the latter, what intervention would you recommend? It is true that her condition is non-progressive and likely to resolve when her stessors are removed. However, her low estrogen state will predispose her to accelerated osteoporosis. Hormonal therapy, then, should be strongly recommended. The optimal dosages of estrogen and progesterone have not been established, but there is concern that the standard postmenopausal HRT regimen (0.625 mg conjugated estrogen plus progestin) may not provide sufficient estrogen. Most authors recommend treating these patients with low dose oral contraceptive agents (35 micrograms ethinyl estradiol and a progestin to protect from unopposed estrogen). Calcium supplementation is also recommended. Women with amenorrhea who want to get pregnant should be referred to a reproductive endocrinologist. Bonus Question: 7. Assume that your patient did experience withdrawal bleeding in response to the progestin challenge. How would this change your differential diagnosis? What further evaluation would you undertake? Unless this was a false positive (a distinct possibility since it would be unexpected with the history), this would indicate adequate estrogen levels in the setting of amenorrhea due to chronic anovulation. Many of these women will have polycystic ovary syndrome, which disrupts the pulsatile secretion of GnRH. The ovaries produce estrogen under FSH
  • 4. stimulation, but, in the absence of the normal LH surge, they do not ovulate and progress to the luteal phase. Thus, they never experience the progestin withdrawal that leads to menses. These women remain at risk for endometrial hyperplasia due to the effect of estrogen unopposed by progestin. The differential diagnosis of this type of amenorrhea is listed in table 4 of the AFP article under hyperandrogenic anovulation in the normogonadotropic amenorrhea category. You would certainly consider these diagnoses sooner in the evaluation if the patient had hirsuitism, obesity, insulin resistance, or acne. In patients with suspected PCOS, the question always arises whether or not to evaluate for androgen producing tumors or adrenal hyperplasia. There is no consensus on this, but I think it is reasonable to reserve this evaluation for women who are virilized or have extremely high testosterone levels (> 200 ng/dl). Note that virilization denotes more than just hirsuitism and acne. A truly virilized woman may have a male somatotype, a male escutcheon (distribution of pubic hair), a deep voice, or clitoromegaly. Primary Reference: 1. Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. American Family Physician. 2006;73(8):1374-1382. http://www.mdconsult.com/das/journal/view/0/N/16186830? ja=535164&PAGE=1.html&issn=0002-838X&source= Additional References: 1. Constantini NW, Warren MP. Menstrual dysfunction in swimmers: a distinct entity. J Clin Endocrinol Metab. 1995;80(9):2740-2744. 2. Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertility & Sterility. 2006;86(5 Suppl):S148-155. Michael Green completed his residency and general medicine fellowship at Beth Israel Hospital and the Harvard Medical School. His scholarly interests include graduate medical education curriculum development and evaluation, evidence-based practice, and life-long self-directed learning. Dr. Green practices general internal medicine and accepts referrals for dyslipidemia and HIV-related lipodystrophy.

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