4 Primary Amenorrhea |
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until completion of puberty allows for a smoother pubertal transition since testosterone is converted to estrogen. Because cryptorchidism is a risk factor for development of malignant germ cell tumors, once puberty is complete, the testes should be removed and hormonal replacement therapy started. Given the absence of a uterus in women with CAIS, estrogen therapy alone is suf cient. In women with partial AIS, gonadectomy should not be delayed given the risk of progressive virilization [1–3].
References
1.\ Welt CK, Barbieri RL. Causes of primary amenorrhea. In: Post TW, editor. Uptodate 2019. Accessed 1 May 2021.
2.\ Klein DA, Paradise SL, Reeder R. Amenorrhea: a systematic approach to diagnosis and management. Am Fam Physician. 2019;100(1):39–48.
3.\ Practice committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2006;86:S148.
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Chapter 5
Secondary Amenorrhea
Pietro Bortoletto and David Reichman
Case
A 34-year-old nulligravida with an 8-month history of secondary amenorrhea presented for evaluation. She reported menarche at age 12 with irregular cycles of 45–60 days intervals. In college she reported acne on her face and chest as well as dark hair growth on her chin and lower abdomen. Given her irregular cycles, she was recommended a levonorgestrel releasing intrauterine device (IUD) which improved her bleeding pattern but did not improve her hair growth or acne. After 5 years of IUD-induced amenorrhea, she discontinued her IUD 8 months prior to presentation but had not experienced any bleeding, spotting, or premenstrual symptoms. She denied excessive exercise, recent weight change, nipple discharge, hotushes, or vision changes. While she was not interested in conceiving at the time of presentation, she expressed signifcant distress regarding the absence of her menses, acne, and hair growth.
Her past medical history is signifcant for migraines without aura. She has no surgical history and uses a topical retinoid to manage her acne and sumatriptan for migraines. She has never been pregnant before and her gynecologic history is unremarkable. Her family history is signifcant for non-insulin-dependent types 2 diabetes and hyperlipidemia. She is a non-smoker, denies illicit drug use, and uses alcohol socially.
On physical exam she was noted to be normotensive with a BMI of 23 kg/m2, there was acne along her face and chest, and thick dark hair along her chin and lower abdomen. There was no evidence of striae, acanthosis nigricans, galactorrhea, or stigmata of thyroid disease. As part of her evaluation, a pelvic ultrasound was performed and revealed an unremarkable, anteverted uterus with a 12-mm
P. Bortoletto · D. Reichman (*)
Reproductive Medicine and Ob/Gyn, The Ronald Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Medical College of Cornell University, New York, NY, USA e-mail: der2005@med.cornell.edu
© Springer Nature Switzerland AG 2023 |
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P. H. Chung, Z. Rosenwaks (eds.), Problem-Focused Reproductive Endocrinology and Infertility, Contemporary Endocrinology, https://doi.org/10.1007/978-3-031-19443-6_5
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P. Bortoletto and D. Reichman |
endometrial stripe, and an antral follicle count of 46 without evidence of ovarian cysts. Laboratory evaluation revealed a negative serum hCG, TSH of 2.8 mIU/L, and prolactin of 4 ng/mL. Random follicle-stimulating hormone (FSH) was 4.2 mIU/ mL, luteinizing hormone (LH) was 8.1 mIU/mL, and estradiol (E2) was 67 pg/ml. An anti-Müllerian hormone returned at 4.7 ng/mL, 17-hydroxyprogesterone was 90 ng/dL, and a total serum testosterone was 110 ng/dL.
Given her menstrual pattern, ultrasound fndings, and serum testing, she was diagnosed with polycystic ovary syndrome. As she was not interested in conceiving at this time but still reported acne and hair growth, she was recommended a combined oral contraceptive pill to control her menstrual cycle and symptoms of hyperandrogenism.
Discussion
Secondary amenorrhea is defned as the absence of menses for more than 3 months in women with regular menstrual cycles or 6 months in those with irregular cycles. In adult patients, the most common cause of secondary amenorrhea is pregnancy followed by hypothalamic (35%), ovarian (40%), and pituitary (17%) disorders [1]. Once pregnancy has been ruled out, a stepwise approach to evaluate each level of the hypothalamic–pituitary–ovary (HPO) axis is essential for effective diagnosis and treatment (Table 5.1).
The frst step in the assessment of a patient presenting with secondary amenorrhea is a thorough review of patient’s behaviors and symptoms. Being that functional hypothalamic amenorrhea is the most common cause of secondary amenorrhea, assessment of recent changes in weight, diet, and exercise pattern is essential. Acute weight loss of as little as 10% below ideal body weight in addition to excessive exercise can precipitate a decrease in pulsatile GnRH secretion leading to amenorrhea [2]. Luckily, women with hypothalamic amenorrhea due to a clear precipitating factor such as weight loss are more likely to have return of their menses with behavioral modifcation [3]. Independent of weight loss and exercise, diets with severe restriction in fat consumption have also been shown to be associated with hypothalamic amenorrhea [4]. Probing of hypothalamic–pituitary disorder specifc symptoms such as headaches, visual feld changes, galactorrhea, and excessive thirst/urination allows for isolation of a likely HPO axis level to further evaluate. Downstream complaints of amenor- rhea-induced estrogen defciency such as hot ushes, vaginal dryness, and mood changes should also be assessed.
Second, it is important to thoroughly assess the patient’s medical, surgical, and reproductive histories as well as medications for potential contributing causes. Systemic illness such as type 1 diabetes mellitus, Celiac disease, Cushing’s disease, and thyroid disorders are commonly associated with changes in menstrual pattern and in many cases amenorrhea may be a presenting feature of the disease [5]. A recent history of cranial or pelvic surgery or radiation may raise suspicion for
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5 Secondary Amenorrhea |
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Table 5.1 Common causes of secondary amenorrhea |
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Causes |
Hypothalamus |
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Functional hypothalamic amenorrhea |
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Intracranial lesions |
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Traumatic brain injury |
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Infltrative or in ammatory disease |
Pituitary |
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Hyperprolactinemia |
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Intracranial lesions |
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Empty Sella syndrome |
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Pituitary apoplexy or infarct |
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Pituitary tumors |
Ovary |
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Primary ovarian insuffciency |
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• Gonadotoxic medication or radiation therapy |
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• Fragile X premutation |
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• Chromosomal abnormalities (i.e., Turner’s syndrome) |
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• Autoimmune disease |
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• Iatrogenic (i.e., surgery) |
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Other |
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Pregnancy |
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Thyroid dysfunction |
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Adrenal disease |
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Systemic illness (i.e., diabetes, Celiac) |
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Polycystic ovary syndrome |
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Cervical stenosis |
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Intrauterine adhesions |
treatment-related complications such as pituitary infarct, intrauterine adhesions, cervical stenosis, or premature ovarian failure. Obstetric history should be assessed for postpartum hemorrhage, retained products of conception, endometritis, and inability to breast-feed postpartum. Finally, medications that act on the HPO axis such as dopamine receptor antagonists, antipsychotics, and selective serotonin reuptake inhibitors must be evaluated as they may potentiate amenorrhea secondary to hyperprolactinemia.
The focus of the physical examination should be on assessing downstream stigmata of hypothalamic–pituitary–ovarian axis disease. A thorough neurologic and ophthalmologic exam can reveal symptoms of intracranial lesions or hypothalamic– pituitary process such as prolactinoma and in ammatory or infltrative diseases that may impact GnRH secretion. Systemic signs of thyroid disease such as hair loss, goiter, dry skin/nails, and fatigue may be more easily identifable as patients may often present with these concurrent complaints. A breast and pelvic exam allows for the assessment of galactorrhea as well as evidence of hypoestrogenism and outlet obstruction such as cervical stenosis. Importantly, targeted evaluation for swollen salivary glands, poor dentition, and callused knuckles should be considered when there is suspicion for disordered eating [6].
The laboratory evaluation for secondary amenorrhea follows a stepwise framework from common to less frequent causes. After pregnancy has been ruled out via serum or urine hCG, the following serum hormones should be evaluated: prolactin, TSH, FSH, and estradiol. Prolactin levels are considered
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P. Bortoletto and D. Reichman |
abnormal if above 40 ng/mL and values in the 20–40 ng/mL should be repeated while the patient is fasting. An abnormal prolactin level should prompt further evaluation of iatrogenic causes (i.e., medications) as well magnetic resonance imaging to evaluate for intracranial lesions (refer to Chap. 11). TSH values that are above 4.5 mIU/L or below 0.5 mIU/L warrant further evaluation of serum T3 and T4 and targeted workup for thyroid disorder. An FSH value greater than 15 mIU/L coupled with hypoestrogenism (hypergonadotropic hypogonadism) may suggest a problem at the level of the ovary such as primary ovarian insuffciency (POI). Suspicion for POI should be followed-up with additional testing to rule out karyotypic abnormalities such as Turner syndrome or fragile X premutation. Patients with low or normal FSH values coupled with hypoestrogenism can be classifed as having hypogonadotropic hypogonadism and can be considered to have functional hypothalamic amenorrhea when systemic illness or other HPO disorders have been ruled out.
In patients with normal prolactin, TSH, FSH, and estradiol levels, such as the case we presented, a search for clinical and laboratory signs of hyperandrogenism should occur. Evidence of hirsutism, male pattern balding, acne, or virilization should warrant evaluation of serum androgens with a total testosterone and 17-hydroxyprogesterone (17-OHP). Elevated total testosterone or 17-OHP should prompt evaluation for androgen-secreting tumors, ovarian hyperthecosis, and congenital adrenal hyperplasia by a specialist.
Finally, in patients with normal serum testing and without signs of hyperandrogenism dynamic testing of the uterus and out ow tract should be considered. When pelvic ultrasound is available, a thickened endometrial stripe may serve to demonstrate suffciently high estradiol levels. Oral progestins can then be used to withdraw the lining. In an appropriately estrogenized and proliferative endometrium with a patent out ow tract bleeding should occur within 2 weeks following cessation of an oral progestin. If endometrial lining is thin on pelvic ultrasound which is a concern for hypoestrogenism, an oral estrogen has to be added to effect bleeding. Should bleeding not occur, evaluation for cervical stenosis and intrauterine pathology should be pursued. In-offce attempts at cannulation of the cervix and distending the uterine cavity via saline infusion sonogram can provide valuable information about potential for a surgical treatment for adhesive disease.
In summary, secondary amenorrhea is a common clinical scenario with a myriad of causes and inciting factors. An understanding of what the common and less common etiologies allows for a stepwise approach to evaluation. A thorough review of a patient’s symptoms and history is often the most important clue to isolate where along the hypothalamus–pituitary–ovary axis a defect may occur. Thoughtful physical examination and targeted laboratory testing will further strengthen the diagnosis and allow for appropriate treatment to be undertaken.
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