CHAPTER 11 A. Reza Radjabi and David L. Keefe Department of Obstetrics and Gynecology, NYU Langone Medical Center, New York, NY, USA Amenorrhea can be a transient, intermittent, or a permanent condition resulting from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina. Amenorrhea can be classified as either primary or as secondary [1]. Primary amenorrhea is defined as the absence of menses at age 15 years in the presence of normal growth and secondary sexual characteristics or alternatively by age 13 years, if no menses have occurred and there is a complete absence of secondary sexual characteristics [2]. Secondary amenorrhea is defined as absence of menses for more than three months in girls or women who previously had regular menstrual cycles or six months in girls or women who had irregular menses [3, 4]. The list of possible etiologies is extensive, but most causes they fall into a limited number of categories and therefore the diagnosis of amenorrhea is subject to a logic and systematic approach. The basic principles in menstrual function provide a framework to understand the causes of amenhorrhea. Amenorrhea can be classified based upon the level of control of the menstrual cycle; hypothalamus and pituitary, ovary, and uterus and vagina [5, 6]. In addition, steroid receptor abnormalities and deficiencies in enzymes of steroidogenesis cause primary amenorrhea at the level of the ovary and the adrenal gland [7]. The basic requirements for normal menstrual function thus include four anatomically and functionally distinct structural components – the genital outflow tract including the uterus, the ovary, the pituitary, and the hypothalamus – thus providing a natural and useful hierarchy for organizing the diagnostic evaluation of amenorrhea. Accordingly, the many causes of amenorrhea can be categorized according to the site or level of the disorder or disturbance [2, 8]. A differential diagnosis for amenorrhea can be developed based on requirements for normal menses and from the medical history and physical examination [2, 9]. The first step is to obtain a comprehensive history [6]. The history surrounding the onset of amenorrhea, cyclic pelvis or lower abdominal pain or urinary complaints may provide important diagnostic clues [5, 9, 10]. The physical examination starts with the overall evaluation of the body habitus to investigate possible causes of amenorrhea arising from nutrition disorders, physical, psychological or emotional stress and obesity [5, 12]. Examination of the skin and the thyroid gland are important [7]. The presence of pubic hair is a sign of androgen production or exposure [13]. The skin may demonstrate evidence of hypercarotenemia, acanthosis nigrans, acne, or hirsutism [14]. Signs of virilization, including deepening of the voice, increased muscle mass, clitoromegaly, fronto‐temporal balding, or decreased breast size, suggest neoplasm of ovarian or adrenal origin, or ovarian hyperthecosis [9]. Examination of the breast demands special attention [14]. Breast development reflects estrogen exposure and arrested breast development suggests disruption of the hypothalamus‐pituitary‐ovarian (HPO) axis [9, 15]. Physical examination of the genital anatomy includes investigation of the genital outflow tract and the uterus. In women with primary amenorrhea, symptoms of obstructed menses and a blind or absent vagina may have a transverse vaginal septum or imperforate hymen. Presence of androgenization with no outflow suggests Müllerian agenesis. Scant or absent pubic hair suggests Androgen Insensitivity Syndrome (AIS) [1, 7, 8]. The arcuate nucleus located in the medial basal hypothalamus secretes gonadotropin releasing hormones (GnRH) in a pulsatile fashion. GnRH stimulates gonadotrophs in the anterior pituitary to synthesize, store, and secrete follicle stimulating hormone (FSH) and luteinizing hormone (LH). These gonadotropins enter the peripheral circulation and act on the ovary to stimulate both follicular development and ovarian hormone production, including estrogen, progesterone, androgens, and inhibin. Inhibin blocks FSH synthesis and secretion [15, 16]. Development of mature follicle results in a rapid rise in estrogen levels, acting positively at the pituitary cogenerate a mid‐cycle surge in LH release and simultaneously stimulate the development of a thickened, proliferative endometrial lining. Following ovulation, LH stimulates luteinization of the follicular granulose cell and surrounding theca cells to form the corpus luteum. The corpus luteum produces estrogen and progesterone. Progesterone changes the endometrium in a secretory pattern. If pregnancy does not occur, then progesterone and estrogen ceases, corpus lute regresses, and endometrial sloughing occurs. If pregnancy occurs then human chorionic gonadotropin (hCG) is secreted from syncytiotrophoblast and the corpus luteum is saved during early pregnancy because of similarity in the structure of hCG compared to LH [15]. Imperforate hymen and transverse vaginal septum are outflow tract malformations that typically present with acute pain in an early teenager who has breast development but fails to menstruate. Mayer‐Rokitansky‐Kuester‐Hauser (MRKH) syndrome, also known as Müllerian agenesis refers to congenital absence of the vagina with variable uterine development. It is usually accompanied by cervical and uterine agenesis; 7–10% of women with MRKH syndrome have a normal but obstructed or rudimentary uterus with functional endometrium, resulting in cyclic pain [2, 9]. The defect results from agenesis or hypoplasia of the Müllerian duct system [5]. Patients typically present in their late teens with normal breast development, normal pubic hair development and in most cases amenorrhea is generally the only complaint. Imaging of the urinary tract should be performed in all patients because approximately 30% of the patients have simultaneous renal anomalies. Skeletal abnormalities are also commonly associated with MRKH. Vaginal dilator therapy can usually create a functional vagina [1, 9]. Complete androgen insensitivity syndrome (CAIS) is an X‐linked recessive disorder occurring in genetically affected men and resulting in phenotypic women. Testes are present and secrete normal male levels of testosterone and anti‐Müllerian hormone (AMH). AMH results in regression of Müllerian structures. Masculinization fails to occur because of an androgen receptor defect. Like MRKH patients, CAIS patients present in their late teens with normal breast development and complains of amenorrhea. Patients with CAIS will have on physical exam sparse pubic and axillary hair, which differentiates CAIS from MRKH on examination, and testes are often palpable in the inguinal region or in the abdomen. Serum testosterone is usually more than 200 ng dl−1 which is in the normal male range and CAIS patients have 46, XY karyotype [9, 20]. CAIS patients have an incidence of gonadal malignancy of 22%, which occurs usually after age 20. For this reason gonadectomy is preformed after pubertal maturation and epiphyseal closure. Vaginal dilator therapy if offered to create functional vagina. Ashermann syndrome, also known as intrauterine synechiae, is most commonly associated with aggressive postpartum curettage or abortion [22]. Other risk factors than can contribute to Ashermann syndrome include uterine and cervical surgeries, including cesarean section, septoplasty, myomectomy, and cone procedures [22]. Overall the diagnosis of outflow tract abnormalities can be assisted with the instrumentation of a sonohysterogram, hysteroscopy, hysterosalpingogram, or a MRI, if there is clinical suspicion for Müllerian anomalies. Turner syndrome is caused by loss of part or all of an X chromosome [23]. Approximately 60% of Turner syndrome patients are 45, X. The other 40% include karyotype abnormalities such as 45,X/46,XX mosaics, 46,XXqi isochromosome, and 46,XXp‐short arm deletion. Internal and external genitalia develop normally for females, while primordial follicles undergo accelerated atresia and oocytes are depleted before puberty [24]. This results in lack of estrogen leading to failure of breast development, osteoporosis and fractures. Appropriate estrogen replacement therapy starting in the second decade of life, and continued until the age of menopause, can help to prevent bone demineralization. Patients with Turner syndrome whose karyotype includes a Y chromosome (such as 45,X/46,XY mosaicism) are at increased risk for gonadoblastoma and therefore prophylactic gonadectomy is advised [29, 30]. Patients with Turner syndrome are at increased risk for cardiovascular malformations, including aortic valvular disease, aortic arch anomalies, pulmonary or systemic venous abnormalities, ventricular septal defects, and hypoplastic left heart syndrome. Patients are at risk for aortic dilatation and dissection, particularly during pregnancy [13, 23, 25]. Mosaicism refers to heterogeneous expression of a disease at the cellular or tissue level, resulting from cell‐specific differences in the expression of a mutation or the presence of a chromosome aberration. This involves partial deletions or rearrangements of one chromosome and can cause a wide range of gonadal dysfunction, from gonadal dysgenesis to premature ovarian insufficiency (POI) [9, 26, 27]. These disorders result in premature depletion of all ovarian oocytes and follicles early in embryonic development. All patients are phenotypic women of normal height who fail to undergo puberty. Patients with Swyer syndrome (46, XY gonadal dysgenesis) require removal of their gonadal streaks to prevent malignancy [3, 28]. CYP17 Deficiency is a rare autosomal recessive disorder that can affect 46, XY or XX individuals. The lack of 17 alpha‐hydroxylase and 17.20 hydroxylase activities results in both gonadal and adrenal insufficiencies. XY individuals are phenotypic women but lack a uterus because of AMH secretion. There is an increase shift of mineralocorticoid production with hypertension, hypokalemia, and hypergonadotropic hypogonadism [28, 29]. POI is defined as the development of hypergonadotropic hypogonadism before the age of 40 years [31]. The presenting symptoms are similar to those of menopause. In POI there is impaired ovarian responsiveness to exogenous or endogenous gonadotropin stimulation and it is a continuum of impaired ovarian function. X chromosome abnormalities, including short‐ or long‐arm deletions or mosaicism are not severe enough to cause primary gonadal dysgenesis but may manifest as POI. Obtaining a karyotype is recommended since 13% of women less than 30 years of age with spontaneous POI have abnormal karyotype, even though the majority of POI patients are idiopathic. It is important to obtain a detailed family history in POI and evaluate the risk of adrenal insufficiency, since 14% of patients with familial POI and 2% of isolated POI have permutations in the fragile X syndrome gene (FMR1) and 4% have steroidogenic cell autoimmunity [26, 31
Amenorrhea
Background
Definition
Clinical questions
Menstrual physiology
Outflow tract abnormalities resulting in primary amenorrhea
Outflow tract abnormalities resulting in secondary amenorrhea
Endocrine disorders
Hypergonadotropic primary amenorrhea
Mosaicism
Pure gonadal dysgenesis
Hypergonadotropic secondary amenorrhea
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