Cme Review Article 26

CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA PRA Category 1 CreditsTM can be earned in 2014. Instructions for how CME credits can be earned appear on the last page of the Table of Contents.

Primary Amenorrhea: Diagnosis and Management Courtney A. Marsh, MD, MPH,* and Frances W. Grimstad, MD† *Clinical Assistant Professor, and †Resident Physician, Department of Obstetrics and Gynecology, University of Kansas, Kansas City, KS

Puberty is a defining time of many adolescents’ lives. It is a series of events that includes thelarche, pubarche, and menarche. Primary amenorrhea is the absence of menarche. There are numerous etiologies including outflow tract obstructions, gonadal dysgenesis, and anomalies of the hypothalamic axis. This review’s aims are to define primary amenorrhea and describe the various causes, their workups, associated comorbidities, and treatment options. At the end, a generalist should be able to perform an assessment of an adolescent who presents with primary amenorrhea and, if warranted, begin initial treatment. Target Audience: Obstetricians and gynecologists, family physicians Learning Objectives: After completing this CME activity, physicians should be better able to perform and assess the findings of an initial workup on a patient with primary amenorrhea, identify the appropriate referral providers, and provide appropriate basic treatment for patients with primary amenorrhea.

Menses is considered by many to be the defining Primary amenorrhea can stem from many physio- point of female puberty. The initiation of menses is a logic sources. However, the first thing to rule out is complex process involving an intact hypothalamic pitu- pregnancy. Because a patient may ovulate before men- itary axis, working ovaries, and a functional outflow struation is witnessed, it is important to check a preg- tract. With this review, we aim to improve understand- nancy test even in patients who deny sexual activity. ing of differential diagnosis, workup, and treatment of The broad differential diagnoses for primary amen- primary amenorrhea in the general gynecology practice. orrhea (Fig. 1) are as follows: Primary amenorrhea is diagnosed by meeting 1 of 2 • anomalies of the outflow tract (uterus, vagina, criteria: hymen), • no period by the age of 14 years in the absence of • anomalies of the gonads, and growth or development of secondary sexual char- • central anomalies (hypothalamic-pituitary axis). acteristics, or • no period by age 16 years regardless of the presence of normal growth and development with ANOMALIES OF THE OUTFLOW TRACT the appearance of secondary sex characteristics.1 Normal menses require a patent outflow tract. This tract is established in utero. The genital tract is formed from the All authors and staff in a position to control the content of this midline fusion of the paired mu¨llerian (paramesonephric) CME activity and their spouses/life partners (if any) have dis- ducts to form the uterus, cervix, and upper vagina. closed that they have no financial relationships with, or financial Vertical fusion of the developing ductal system with interests in, any commercial organizations pertaining to this educa- the invaginating urogenital sinus forms the lower va- tional activity. gina and introitus.3 Correspondence requests to: Courtney A. Marsh MD, MPH, Department of Obstetrics and Gynecology, University of Kansas Structural anomalies that cause primary amenorrhea Medical Center, 3901 Rainbow Blvd MS 2028, Kansas City, can impact any of the structures from the uterus down Kansas 66160. E-mail: [email protected]. to the hymenal ring (Fig. 2). They cause roughly

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outpouching at the vaginal introitus. Resection is the definitive treatment, with possible postoperative stent placement. The thicker and higher septae require a stent placed for a period.4,5 Surgery is considered definitive treatment for the dysmenorrhea and/or dyspareunia. The most common long-term complication after resection is stenosis.4 The second 2 causes of structural anomalies, mu¨llerian agenesis and androgen insensitivity syndrome (AIS), typically present with asymptomatic amenorrhea as the outflow tract anomalies are due to alackofmu¨llerian structures. FIG. 1. A breakdown of the most common causes of primary amenorrhea.2

Mu¨llerian Agenesis 1 20% of the cases of primary amenorrhea. Patients Mu¨llerian agenesis or Mayer-Rokitansky-Kuster- with these anomalies have an intact hypothalamic- Hauser (MRKH) syndrome is a failure of the mu¨llerian pituitary-gonadal axis. tract to develop. It can be a failure of any of the struc- Imperforate hymen and transverse vaginal septum tures along the mu¨llerian tract, which includes the for- are causes of distal outflow obstruction. They pres- mation of the fallopian tubes, uterus, cervix, and ent with cyclic pain during the onset of puberty. This proximal two-thirds of the vagina. Vaginal agenesis pain is due to cryptomenorrhagia. However, other occurs in roughly 1:4000 to 1:10,000 females. It is than the obstruction, these patients will have normal most commonly associated with uterine agenesis.7,8 pubertal development with normal pubic hair and Patients with MRKH will typically present late in ado- breast development. lescence with their only complaint as amenorrhea.1 They may have uterine remnants present on imaging, including possible uterine horns from the failure of fu- Imperforate Hymen sion. Most will have rudimentary mu¨llerian bulbs that 7 An imperforate hymen is usually noted as a bluish lack an endometrial cavity. If physical examination bulging mass at the entrance to the vagina. This is and abdominal ultrasound are suggestive of MRKH caused by the hematocolpos. The treatment is simple but the patient complains of cyclic pain, magnetic reso- resection. It is best performed in adolescence as the nance imaging (MRI) is useful in detecting endome- estrogenization improves healing.4 A cruciate incision trium in remnant uterine horns. Uterine remnants with is performed to allow for drainage of menstrual blood, active endometrial tissue may require surgical removal, and then the hymen is excised. Patients with this disor- which can be performed in a minimally invasive fash- 9,10 der can go on to have normal menstrual function. ion. Females with MRKH have normal external genitalia, normal ovaries, and hormonal patterns. Patients with MRKH can also present with renal Transverse Vaginal Septum anomalies (unilateral agenesis, horseshoe kidney, or duplicating collecting systems) and skeletal anomalies A transverse vaginal septum is usually caused by the (involving the vertebrae, ribs, or pelvis). It is important failure of the vaginal plate to fuse and dissolve as it meets the mu¨llerian tract.1 The mu¨llerian duct usually makes up the upper two-thirds of the vaginal canal, and the lower one-third comes from the urogenital sinus. The canal is usually formed by the third month of development.5 Septa can lie anywhere along the length of the vaginal cavity.6 The most common location is high in the vaginal cavity. Most are one to several mil- limeters thick. It is a rare anomaly, found in 1:2100 to 1:72,000 females.5 A shortened blind vaginal pouch will be noted on examination. Unlike an imperforate hymen, the Valsalva maneuver will not cause an FIG. 2. The common causes of outflow tract anomalies.

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Primary Amenorrhea • CME Review Article 605 that once these patients are diagnosed, imaging should report libido and the ability to experience orgasm.12 be performed to assess for any of these extragenital The majority of the subjects will either be of average malformations. or tall stature. In a study by Wisniewski,12 57% of pa- The treatment for these patients is multidisciplin- tients with complete AIS were at greater than or equal ary. Psychosocial counseling helps individuals cope to the 90th percentile of height for the range of their with diagnosis and provides a forum for discussion control adult females. issues with sexuality. Support groups with patients Treatment of AIS is multifold. Similar to mu¨llerian who share the diagnosis may also be useful.7 Vaginal agenesis, it is important to refer these patients to the agenesis can be treated with serial vaginal dilation or appropriate specialists for care including psychoso- surgery and should be managed by a trained provider. cial counseling, possible creation of the neovagina, These should be performed when the patient is emo- and removal of the intra-abdominal testes. Patients tionally mature enough to commit to the treatment.7 with intra-abdominal testes have a 5% to 10% inci- A retrospective study of 245 women who underwent dence of gonadal tumors.1 In 1 study, the median age creation of a neovagina with dilators noted a 94.9% of gonadectomy was 5.5 years; 2 cases of carcinoma success rate in the achievement of adequate length (of 44 patients) were noted to have carcinoma in situ; (>6 cm).11 Routine gynecologic care is still indicated, however, these patients both had a postpubertal gonad- as the vaginal cavity is still at risk for infection. ectomy. The authors concluded that the risk for malig- Neovaginas crafted from bowel are at risk for malignant transformation was low prior to puberty and that nancy, colitis, and ulceration; an annual speculum ex- patients could safely delay gonadectomy until that amination is warranted for screening. Routine vaginal time.12 cytologic testing, however, is not recommended.7 As MRKH and AIS are difficult to distinguish from It is crucial to refer these patients early to special- physical examination alone, obtaining a peripheral ists for the mental, emotional, and physical manage- karyotype and serum testosterone level can distin- ment of the disorder. Although the patient will not guish these syndromes. Females with MRKH will be able to bear children, future fertility is possible have a 46XX karyotype and low testosterone level; with the use of advanced reproductive technology.7 individuals with AIS will have a 46XY karyotype and testosterone level in the normal male range. Androgen Insensitivity Syndrome ANOMALIES OF THE GONADS Androgen insensitivity syndrome is a disorder of the androgen receptor. An inactivating mutation in Amenorrhea caused at the ovarian level is due to the gene encoding for the intracellular androgen re- the absence of follicles capable of producing estra- ceptor leads to end-organ insensitivity to androgens. diol (Fig. 3). The patients are genetically 46XY; they have testes, Gonadal Dysgenesis which produce testosterone and anti–mu¨llerian hormone. However, because of receptor insensitivity, Gonadal dysgenesis is the most frequent cause of 1 there is no masculinization of the external genitalia, primary amenorrhea (30%–40%). It is due to an in- leading to female external genitalia. Because the tes- complete or defective formation of the gonads, which tes continue to produce anti–mu¨llerian hormone, the is secondary to problems with germ cell migration mu¨llerian tract never forms. The patients have a short blind vagina, similar to patients with MRKH. They will have breast development secondary to peripheral conversion of androgens to estrogen.1,7 Most will have sparse pubic hair due to limited activity of the androgen receptor, even in complete AIS, which is very rare. In 2011, only 20 patients were noted in the Johns Hop- kins Pediatric Endocrinology Clinic database.12 In all AIS patients, the testes will not fully descend and usually end up intra-abdominal, often in the inguinal canals. Greater than 50% of patients present with inguinal her- nias.13 As long as the testes are present, the patients will have normal male levels of testosterone.7,13 Even with end-organ resistance to testosterone, patients can still FIG. 3. Breakdown of the anomalies of the gonads.

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 606 Obstetrical and Gynecological Survey and/or organization. These women have elevated showing abnormal levels of -human chorionic gonad- follicle-stimulating hormone (FSH) due to a lack of otropin, unconjugated estriol, and -fetal protein can ovarian folliculogenesis, leading to decreased nega- be suggestive of Turner syndrome. A karyotype is de- tive feedback on FSH from estradiol and inhibins A finitive for diagnosis in most cases.16 and B. These patients classically present with short stat- There are many types of gonadal dysgenesis: pure, ure, a webbed neck, low-set ears, widely spaced nip- partial, and mixed. Pure gonadal dysgenesis patients ples (“shield chest”), and short fourth metacarpals have streak gonads and are either 45XO (Turner syn- (Fig. 4). If these patients have not already been iden- drome), 46XX, or 46XY (Swyer syndrome). Partial tified in childhood, they will present with primary (bilateral dysgenic gonads) and mixed (1 streak and amenorrhea and absent secondary sex characteristics, 1 dysgenic gonad) are variations on the above and of- although they may have some amount of axillary and ten are diagnosed only via biopsy or removal of the pubic hair secondary to adrenal production of dehy- gonads.10 droepiandrosterone.13 Their growth rate will slow compared with their peers as early as 18 months. In Pure Gonadal Dysgenesis 1 cohort, 104 of 150 patients who had presented with Turner syndrome as teenagers had decreased growth Turner Syndrome velocity earlier on in life that was overlooked.16 Turner syndrome patients will have health issues Turner syndrome accounts for roughly two-thirds of 14 unrelated to their genital anomalies. Roughly one- cases of gonadal dysgenesis. The incidence has been third will have cardiovascular anomalies (bicuspid reported in literature to be 1 per 2000 to 1 per 4000 aortic valve, coarctation of the aorta, mitral valve live-born girls and 1 per 15 spontaneous abor- 1 10,13,15 prolapse, and aortic aneurysm). More than 80 cases tions. The karyotype is usually 45XO, although of aortic dissection have been documented.16 Common they can also have 45X/46XX or 45X/46XY mosai- renal anomalies include horseshoe kidney, unilateral cism, or X-related anomalies such as deletions, ring, 1 agenesis or pelvic kidney, rotational abnormalities, and isochromosomes. In Turner syndrome, the germ and partial or complete duplication of collecting sys- cells of the ovaries experience normal migration and tems.1 These can happen in up to 40% of patients.16 mitosis, but the oogonia do not undergo meiosis, lead- Autoimmune disorders are also common including ing to rapid loss of oocytes, fibrosis, and a streak ovary type 1 diabetes and thyroiditis.1 Hypothyroidism oc- by birth (Table 1). curs in up to 15% to 30% of patients.16 Strabismus These patients can be diagnosed prenatally. Ultra- and cataracts more commonly occur in patients with sound findings of fetal edema and genetic screening Turner syndrome. Obesity is another common prob- lem.16 Because of the increased risk for these prob- TABLE 1 Most Common Comorbidities Associated With Turner Syndrome lems, patients with Turner syndrome should be screened with a renal ultrasound, an echocardiogram, Major Turner Syndrome Comorbidities and ophthalmologic examinations. They should be Cardiovascular Bicuspid aortic valve monitored for hypertension, diabetes, and thyroid Coarctation of dysfunction.13,16 Thyroid disorder usually presents the aorta Mitral valve prolapse in the third decade, so screening is recommended to Aortic aneurysm begin at 10 years in asymptomatic patients. Patients Renal Horseshoe kidney are also at increased risk for anxiety and poor self- Unilateral agenesis esteem.16 Early referrals to counselors and support Pelvic kidney groups should be offered. Rotational abnormalities Those who have mosaicism with a Y chromosome Partial or complete have an increased risk of malignant transformation of duplication of the gonads. Thirty percent are likely to have tumors collecting systems by age 30 years (the highest rate, 50%, in 1 study was Autoimmune Type 1 diabetes in those with female external genitalia17), and of Thyroiditis 10 Ocular Strabismus those, up to 60% will have malignant transformation. Cataracts Estrogen and cyclic progesterone replacement will Other Obesity result in normal pubertal development. Timing is im- Anxiety and poor portant, as therapy should be commenced around 13 self-esteem to 14 years old. This is to maximize the growth

of normal to tall stature and present with amenorrhea and absent secondary sex characteristics. This is different from premature ovarian insufficiency in which patients do develop secondary sex characteristics. Patients with 46XX gonadal dysgenesis will have a normal karyotype and streak gonads noted on imaging.13 These patients should be screened for sensorineural hearing loss as they may have an autosomal recessive disorder—Perrault syndrome.10 Treatment is similar to that of women with Turner syndrome involving estrogen and cyclic progesterone (or unopposed estrogen if no breasts).

Swyer Syndrome 46XY gonadal dysgenesis is called Swyer syndrome. It is a rare condition; the gonads produce neither anti– FIG. 4. Common physical manifestations of Turner Syndrome. mu¨llerian hormone nor androgens. As a result, they have normal internal and external female genitalia. Some will have streak gonads, whereas others will have potential of the patient, as well as provide patient with a nonfunctional testicular tissue.15 Roughly 10% to 20% roughly age-appropriate pubertal development. The es- of these cases are due to a mutation in the SRY gene.1,15 trogen therapy should start with a low dose, increasing 1 They present as phenotypically female with primary gradually as the Tanner stages are experienced. Unop- amenorrhea and delayed secondary sex characteris- posed estrogen should be started in those with absent tics. Treatment is 2-fold: gonadectomy, as these pa- breast development, as progesterone will cause mis- tients have a high risk of malignant transformation shapen tubular breasts. Recombinant human growth (20%–30%),1,10 and hormone replacement therapy, hormone has also been used to improve the height of similar to women with Turner syndrome. Because these Turner syndrome patients. The results of those treated patients maintain normal mu¨llerian structures, it is pos- have ranged from no gain to 11.9 cm of added height. sible for them to bear children with appropriate hor- However, an ideal dose and duration of treatment have monal therapy and assisted reproductive technology.15 yet to be established. Both hormone replacement therapy and recombinant human growth hormone treatment Polycystic Ovary Syndrome may improve bone mass.10,16 Patients with Turner syndrome tend to have a Polycystic ovary syndrome (PCOS) is characterized shorter life expectancy, usually owing to diabetes by hyperandrogenism, ovulatory dysfunction, and and heart disease. In 1 cohort, the mean age at death polycystic ovaries. The Endocrine Society guidelines was 27.9 ± 25.5 years, with the range being birth to require the following for diagnosis: presence of clini- 80 years.16 cal and/or biochemical evidence of hyperandrogenism Because of increased risk of cardiac anomalies, (after excluding other etiologies), in the presence of preconception coordination of care between a mater- persistent oligomenorrhea.16 The incidence ranges nal fetal medicine and cardiology specialist is needed based on criteria but is roughly 7% of reproductive- before attempting pregnancy. If childbearing is a via- aged women.18 Insulin resistance is common among ble option, females with Turner syndrome should be women with PCOS. Hormonally, PCOS women have referred to a reproductive endocrinologist as they decreased levels of sex hormone–binding globulin typically need assisted reproductive technology to and increased levels of bioavailable circulating andro- conceive. gens. While PCOS is typically associated with second- The other one-third of patients with gonadal dys- ary amenorrhea, it is possible for adolescents with genesis can have either 46XX or 46XY karyotype. PCOS to present with primary amenorrhea. These patients will usually have the classic findings of PCOS including hyperandrogenism (hirsutism and acne), insulin 46XX Gonadal Dysgenesis resistance (acanthosis nigricans), metabolic syndrome, 46XX gonadal dysgenesis is likely due to autosomal and polycystic ovaries on ultrasound.18 Treatment is pri- genes. These women have otherwise normal pheno- marily centered around management of symptoms and type with no other somatic anomalies.1 They will be restoration of menses. If associated with overweight or

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 608 Obstetrical and Gynecological Survey obesity, weight loss is the first-line treatment. Combined are multifold and can include prolactinomas, hypothy- oral contraceptives are useful for long-term manage- roidism, or dopaminergic drugs. Prolactinomas are be- ment as they suppress luteinizing hormone (LH) secre- nign tumors of the pituitary gland and are diagnosed tion, decrease ovarian androgen secretion, and increase through pituitary MRI. circulating sex hormone–binding globulin.18 Other Functional prolactinomas will present with hyper- virilizing etiologies must be excluded before diagnosis prolactinemia. If the prolactin is mildly elevated of PCOS can be made. (20–40), then the laboratory test should be repeated in a fasting state. If the prolactin is persistently elevated or highly elevated (>100) on initial testing, a pituitary CENTRAL ANOMALIES MRI should be performed to rule out macroadenoma. Disorders of the Anterior Pituitary Patients with a prolactinoma may have galactorrhea or ocular headaches, although these are not always These disorders are also rare prior to puberty and present.1 Patients with a macroadenoma may also will normally present with secondary amenorrhea. Hy- present with symptoms of pituitary stalk compres- pothalamic amenorrhea can present as primary amen- sion including headaches, visual disturbances (pe- orrhea and will be mentioned briefly. ripheral hemianopsia), delayed development, poor growth, and diabetes insipidus.13 Hyperprolactinemia With hyperprolactinemia, it is important to treat the Hyperprolactinemia can be caused by multiple sources patient’s symptoms and not just the prolactin level. (Table 2) and is a common cause of amenorrhea. Prolac- Discussing long-term goals, including fertility, is tin is secreted by the pituitary episodically. Prolactin is needed to help patients obtain the appropriate treat- inhibited by dopamine.13 Causes of hyperprolactinemia ment. Referral to an endocrine specialist is important in creating a treatment plan. Dopamine agonists are the primary treatment for hyperprolactinemia. They TABLE 2 have been shown to decrease prolactin, resume men- An Overview of the Etiologies of Hyperprolactinemia ses, increase fertility, and increase bone absorption Etiologies of hyperprolactinemia of calcium. In those patients not seeking fertility, Idiopathic hyperprolactinemia (most common) combined oral contraceptives can help restore men- • Physiologic activities ○ strual regularity to patients with hyperprolactinemia, Pregnancy 1 ○ Sleep as well as providing contraception. ○ Eating ○ Coitus Empty Sella Syndrome ○ Stimulation of breasts • Neoplastic causes (ie, prolactinoma) Empty sella syndrome is a rare disorder of the ante- • Medications rior pituitary region and is diagnosed through pituitary ○ Those that increase MRI. The disorder is due to the congenital defect in the ▪ Serotonin sellar diaphragm that permits for extension of the cere- ▪ Norepinephrine ▪ Opioids brospinal fluid in the subarachnoid space into the pitu- ▪ Estrogen itary fossa. It compresses the pituitary stalk, disrupting 1 ▪ TRH the hypothalamic-pituitary-ovarian axis. ○ Those that block dopamine receptor action (phenothiazines) Hypothalamic Disorders ○ Those that deplete catecholamine levels (monoamine oxidase inhibitors) Hypothalamic disorders present with hypogonadotropic • Hypothalamic-pituitary disorders hypogonadism. These patients have low LH and FSH ○ Craniopharyngioma and other tumors (<5 mIU/mL) due to central suppression of gonadotropin- ○ Infiltrative conditions (such as sarcoidosis, tuberculosis) 3 ○ Pituitary-stalk resection releasing hormone (GnRH). ○ Multiple sclerosis ○ Empty-sella syndrome Functional Hypothalamic Amenorrhea • Systemic diseases ○ Hypothyroidism Functional hypothalamic amenorrhea is a constella- ○ Chronic renal failure tion of disorders that inhibit pulsatile release of GnRH, ○ Cushing disease LH, and FSH and include eating disorders, exercise- ○ Acromegaly induced amenorrhea, malnutrition, and stress. It is the- TRH, thyrotropin-releasing hormone. orized that the amenorrhea from all of these disorders,

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Primary Amenorrhea • CME Review Article 609 to some extent, stems from a stress-induced increase in (from papilledema to loss of vision22), delayed develop- cortisol levels from activation of corticotrophin-releasing ment, poor growth, and diabetes insipidus.13 Although hormone.1 They are often a cause of secondary amen- rare, the amenorrhea is caused by the space-occupying orrhea but can cause primary amenorrhea. lesions pressing on the hypothalamus and pituitary. Pa- Anorexia is briefly defined as follows: the refusal to tients with concern for a craniopharyngioma should be maintain body weight within a reference range for referred to a neurosurgeon as the treatment is surgical height and age (<85% of ideal body weight). These pa- resection. Recurrence is common, with 1 retrospective tients will present with hypotension, hypothermia, dry study showing that most recurrences occur within the skin, and lanugo. first 3 postoperative years. With the addition of radia- Bulimia nervosa is briefly defined as episodic binge tion and microsurgical techniques, the recurrence rate eating, consuming abnormally large amounts of food, will likely decrease.22 with a sense of lack of control.1 Malnutrition from other sources can also cause Cranial Radiation amenorrhea. Females with Crohn disease, sickle cell Children who have undergone cranial radiation may anemia, and cystic fibrosis are all at increased risk 13 also have decreased hypothalamic gonadotropins. The for delayed puberty and primary amenorrhea. radiation decreases the pulsatile release of GnRH as Exercise-induced amenorrhea is usually found in well as affecting the release of growth hormone. Men- women who partake in sports that emphasize low body ses is usually restored after completion of therapy.23 weight, such as long-distance running, gymnastics, and 1 These patients will likely have intact ovaries and an ballet. They present with the female athlete triad: outflow tract and can respond to hormonal therapy.13 amenorrhea, disordered eating, and osteoporosis. Pa- tients with eating disorders and malnutrition have Constitutional Delay found that menses seem to return with restoration to Constitutional delay is a delay in puberty where pa- roughly 90% of the ideal body weight.13,19 Although tients go on to have normal puberty, simply at a later some will remain amenorrheic, 1 study postulated this age. It is more common in boys than in girls.24,25 The has to do with patients maintaining a low resting en- mean delay of pubertal onset in 1 study was 2.5 years.25 ergy expenditure even with restoration of weight.19 Patients will often present because of short stature and the lack of secondary sex characteristics.24,26 This is a Kallmann Syndrome diagnosis of exclusion; there is no definitive testing. A rare cause of primary amenorrhea is Kallmann Patients will often have a family history of pubertal de- syndrome. It is an X-linked disorder, which manifests lay. Management includes optimizing growth and im- as delayed growth and sexual development and anos- proving peak bone mass.13,26 mia and may have midline cranial defects. It is due to Summary of key features are shown in Tables 3 mutations in the GnRH receptor. Six genes are respon- and 4. sible for the most common causes, with each gene leading to a different extracranial manifestation in- CONCLUSIONS cluding skeletal anomalies and synkinesis.20,21 This Primary amenorrhea is a concern that affects adoles- prevents migration of the GnRH neurons and the olfac- cents. We review the primary assessment of a female tory neurons.13 They will have normal pubic hair. with primary amenorrhea. Treatment does depend on Their distinctive characteristic is that they cannot per- the etiology; however, there are a few standard prac- ceive smells.1 On physical examination, it is important tices. Outflow tract obstructions, if amenable to resec- to test for anosmia with a noncaustic agent (eg, coffee tion, should be surgically corrected. Females with grounds). Treatment is specific to patient complaint primary amenorrhea will often need hormonal ther- and typically involves sex steroid hormone replace- apy. For patients with a uterus and fully developed ment therapy. breasts, unopposed estrogen increases the risk for endometrial hyperplasia and malignancy. This risk can Craniopharyngiomas be reduced with cyclic progestin to restore cycles. If Craniopharyngiomas are another rare source of hypo- there is inadequate breast development, progestin ther- thalamic amenorrhea. They account for 3% of intracra- apy should be avoided to prevent misshapen, tubular nial neoplasms and only 1% of primary amenorrheas.22 breasts. Patients with persistent hypoestrogenemia are Most present between 6 and 14 years old, usually as an at risk for osteoporosis and should be screened with emergency and causing headaches, visual disturbances dual-energy X-ray absorptiometry (DEXA) and treated

TABLE 3 Review of the Causes of Primary Amenorrhea and Their Primary Signs and Symptoms Disorder Key Features Anomalies of the outflow tract • Normal hormonal cycles and secondary sex characteristics • A lack of initiation of menses Imperforate hymen • Cyclic pain • A bluish bulging mass at the entrance to the vagina Transverse vaginal septum • Cyclic pain • Short blind vaginal pouch • Intact müllerian tract (with possible hematocolpos) on imaging MRKH • Short blind vaginal pouch • Incomplete or absent müllerian tract on imaging AIS • Short blind vaginal pouch • Absent müllerian tract on imaging • Intra-abdominal gonads on imaging • Male levels of testosterone • XY karyotype Anomalies of the gonad • Primary amenorrhea • Absent secondary sex characteristics • Normal outflow tract • Intact müllerian structures and streak gonads on imaging Turner syndrome • Short stature • Characteristic phenotype (webbed neck, low-set ears, “shield chest,” shortened fourth metacarpals) • 45XO (or mosaic) karyotype 46XX gonadal dysgenesis • Normal to tall stature • 46XY karyotype Swyer syndrome • Normal to tall stature • 46XY karyotype PCOS • Normal outflow tracts • Secondary sex characteristics • Hyperandrogenism (hirsutism and/or acne, elevated circulating androgens) • Overweight/obesity • Possible polycystic ovaries on ultrasound • Insulin resistance (acanthosis nigricans) Central anomalies Hyperprolactinemia • Elevated prolactin • MRI may show a prolactinoma • Galactorrhea may be present Empty sella syndrome • Increased cerebrospinal fluid into the subarachnoid space as seen on an MRI, which will compress the pituitary stalk Functional hypothalamic amenorrhea • Anorexia nervosa (patients will present with symptoms of ○ Low body weight, hypotension, hypothermia, dry skin, lanugo the specific etiology) • Bulimia nervosa ○ Low to normal weight ○ History of binge eating and possible purging • Chronic disease causing malnutrition • Exercise-induced amenorrhea ○ Participation in sports, which emphasize low body weight ○ Athletes triad: amenorrhea, disordered eating, and osteoporosis Kallmann syndrome • Anosmia • Possible midline cranial defects Craniopharyngiomas • Diagnosed with imaging after presenting with symptoms of the space-occupying lesion (visual disturbances and headaches) Cranial radiation • Restoration of menses will likely happen soon after completion of the therapy Constitutional delay • Diagnosis of exclusion • Possible history of pubertal onset in the patients female family members

TABLE 4 Initial Workup for a Patient With Primary Amenorrhea Treatment considerations for primary amenorrhea 1. Check a pregnancy test. 2. For patients with a uterus and fully developed breasts, unopposed estrogen increases the risk for endometrial hyperplasia and malignancy. This risk can be reduced with cyclic progestin to restore menstrual cycles. 3. If there is incomplete breast development, progestin therapy should be avoided to prevent misshapen, tubular breasts. 4. Patients with persistent hypoestrogenemia are at risk for osteoporosis and should be screened with DEXA and treated with vitamin D, calcium, and estrogen therapy, if appropriate.* 5. Patients with 46XY karyotype should be screened for intra-abdominal gonadal structures as they have malignant potential and may need to be removed. *Bone density studies of the lumbar spine and hip should be performed if patients have more than 6 to 12 months of hypoestrogenic amenorrhea. Initiation of treatment is still controversial, but there is consensus for treating with vitamin D27,28 A Cochrane review has established that treatment with bisphosphonates is acceptable for pediatric patients with chronic disease, although they did not find a statistical difference in fracture rates. We recommend that additional therapy beyond vitamin D, calcium, and sex steroid hormonal therapy be initiated by a specialist familiar with bisphosphonate use in the adolescent population.29 with vitamin D, calcium, and estrogen therapy, if therapies at the appropriate times, aiming to im- appropriate. For patients who lack a uterus but main- prove their outcomes. tain their ovaries, surrogacy is an option to achieve biological offspring. For those with a functional uterus REFERENCES but gonadal dysgenesis, egg donation and in vitro fer- 1. Marc FA, Speroff L. Clinical Gynecologic Endocrinology and In- fertility. 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