MODERN TRENDS'IltEl~DS Edward Wallach, M.D. Associate Editor FERTILITY AND STERILITY Vol. 30, No. I, July 1978 Copyright © 1978 The American Fertility Society Printed in U.S.A. AMENORRHEA-ETIOLOGIC APPROACH TO DIAGNOSIS PAUL G. McDONOUGH, M.D. Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia 30901 A delay in the initiation of menses at the time nated. All types of normally and ectopically lo­ of puberty or the interruption of an established cated trophoblastic proliferations should be menstrual pattern constitutes amenorrhea. Ces­ thought of collectively and suspected in every pa­ sation of menses normally occurs in the human tient who has a positive test for human chorionic female at the time of menopause. Failure to in­ gonadotropin. If suspicion of trophoblast persists itiate menses, interruption of a normal cyclic pat­ in spite of a negative routine pregnancy test, then tern of menses, or premature cessation of menses the more sensitive ,8-subunit human chorionic constitutes unphysiologic amenorrhea. Arbitrar­ gonadotropin determination should be performed. ily classifying menarchal failure and the inter­ Excluding the presence of active, viable, pro­ ruption of a normal cyclic menstrual pattern into liferating trophoblast in all patients with primary and secondary amenorrhea is largely amenorrhea should be the first consideration be­ semantic, since the same etiologic factors may be fore other etiologies are considered. operative in either instance. Over the past decade the evaluation of amen­ The average age for first menses is 13.5 years. orrhea has been assisted by advances and refine­ Menarche at chronologie ages 11 and 15 are 2 ments in diagnostic techniques. The diagnosis of standard deviations removed from the mean.1 The ovarian failure has been facilitated by the availa­ mean for the normal ovulatory menstrual inter­ bility of sensitive serum gonadotropin measure­ val is 28 days, and ranges around that interval ments. Improved techniques of chromosomal extend from 21 to 44 days.2 The average age for banding ensure a confident diagnosis of the sex cessation of menses is 49, with ranges from 35 to chromosome abnormalities associated with 55 years. Departure from these norms constitutes amenorrhea. Laparoscopic techniques have pro­ at least temporary failure of the cycling mecha­ vided an easy means of visualizing the gonads, nism with clinical amenorrhea. An arbitrary rule and polytomography of the sella turcica assisted of thumb as to what constitutes significant by computerized axial tomography (the CAT pathologic amenorrhea is difficult to define and scan) has improved the early diagnosis of pitui­ has very little use clinically. It is the concern or tary tumors. A specific radioimmunoassay for anxiety of the patient, regardless of the duration serum prolactin has provided a sensitive indicator of amenorrhea, that prompts her visit to the of hypothalamic-pituitary dysfunction and physician. For example, interruption of the cy­ prolactin-secreting pituitary microadenomas. cling mechanism due to pr.egnancy should be Plasma levels of testosterone, growth hormone, diagnosed as soon as possible. A delay of 3 to 6 and cortisol are readily available through com­ months in the diagnosis of other causes of mercial laboratories. The general trend is toward amenorrhea does not create any harm or undue the direct measurement of pituitary polypeptides anxiety for the patient if the presence of preg­ and steroids in blood rather than their counter­ nancy or trophoblastic disease has been elimi- parts or metabolites in urine. This general switchover from urine to blood and from milli­ Received January 3, 1978. *Reprint requests: Paul G. McDonough, M.D., Department of grams to nanograms and picograms has created a Obstetrics and Gynecology, Medical College of Georgia, 1120 new dimension that the physician must master. 15th Street, Augusta, Ga. 30901. Lastly, the isolation of gonadotropin-releasing I 1 I I -v I 2 MCDONOUGH July 1978 hormone (GnRH) and other potent analogs pro­ TABLE 1. Etiology of Amenorrhea vides for a dynamic test of hypothalamic­ Eugonadotropic amenorrhea pituitary function. Nonfunctional uterus In spite of these improvements in diagnostic Congenital (Rokitansky syndrome) Acquired (Asherman's syndrome) techniques, a careful history and physical exami­ Functional uterus with obstruction nation with appropriately selected laboratory Hypergonadotropic amenorrhea studies remain paramount in the evaluation of Chromosomally incompetent ovarian failure (CIOF) Chromosomally competent ovarian failure (CCOF) amenorrhea. The clinician's acumen should in­ 46,XY forms clude a perspective of the different etiologies of Swyer's syndrome (XY gonadal dysgenesis) amenorrhea, their relative frequency, and an Congenital androgen insensitivity syndrome 46,XX forms acute awareness of any particular causes which Autosomal recessive gene may compromise the life-span or fertility of the Environmental factors patient. Autosomal abnormalities Infectious infiltrative disease Autoimmune disease Gonadotropin-resistant ovary (Savage syndrome) ETIOLOGY 17 -Hydroxylase deficiency Hypogonadotropic amenorrhea The etiologies of amenorrhea which preclude Congenital (Kallmann's syndrome) menarche tend to be represented by genetic Acquired causes or anatomical maldevelopments of the Pituitary tumors and necrosis Drug-induced amenorrhea genital tract. In contrast, the interruption of an Psychogenic amenorrhea established cyclic pattern of menses is usually Stress-induced tonic LH (short-term) psychogenic in origin. One should appreciate the Stress-induced tonic LH (long-term) Hypogonadotropism (stress, nutrition) high frequency of genetic causes in the patient Hypogonadotropic hyperprolactinemia with primary amenorrhea and the relatively high Systemic illness-endocrine frequency of psychogenic factors in patients with Thyroid (hyper, hypo) Adrenal (hyper, hypo) secondary amenorrhea. The approach to an Systemic illness-non-endocrine evaluation of these high-frequency groups will be Amenorrhea and galactorrhea stressed. Androgen excess Adrenal tumor The spectrum of pathology seen in association Congenital adrenal hyperplasia with amenorrhea is varied, but certain well­ Virilizing ovarian tumors defined categories are recognizable. These Androgenic ovary syndrome categories can be broadly grouped into eugonad­ otropic amenorrhea, hypergonadotropic amen­ orrhea, hypogonadotropic amenorrhea, and rian anlagen. The bilateral hypoplastic discrete amenorrhea occurring in association with andro­ uteri seen in these individuals are associated with gen excess (Table 1). The separation of the total vaginal agenesis. Ovarian endocrine func­ amenorrheas into these four large groups facili­ tion and exocrine function are normal. The failure tates the diagnosis. The first two groups are more of the two Mullerian anlagen to fuse completely often associated with menarchal delay, whereas eliminates the natural stimulus for normal the hypogonadotropic group usually presents canalization of the vagina by upgrowth of urogen­ with secondary amenorrhea. Disorders of andro­ ital sinus epithelium. Developmental abnor­ gen excess may produce primary or secondary malities of the kidneys occur frequently in these amenorrhea, but are more frequently associated individuals. The most frequent renal malforma­ with the latter. tion is a solitary ectopic kidney located in the pel­ vis. Skeletal abnormalities such as mild to severe Eugonadotropic Amenorrhea scoliosis and Klippel-Feil deformity occasionally occur in association with the Rokitansky­ Nonfunctional Uterus Kuster-Hauser syndrome. The etiology of this syndrome remains obscure. The high frequency of Congenital. sporadic cases tends to incriminate an autosomal recessive gene or an environmental factor affect­ The most frequent anatomical cause of primary ing early development of the mesonephric and amenorrhea is the Rokitansky-Kuster-Hauser paramesonephric system. Identical twins discor­ syndrome. 3 • 4 This syndrome is characterized by dant for Rokitansky-Kuster-Hauser syndrome hypoplasia and failure of fusion of the two Mulle- have been reviewed by Lischke et al. 5 Discordance Vol. 30, No.1 AMENORRHEA-ETIOLOGIC APPROACH TO DIAGNOSIS 3 in monozygotic twins suggests that differential diagnosis. On a few occasions after a missed abor­ environmental factors are operative in utero. tion, nonviable hyalinized or calcific villi may Individuals with the Rokitansky-Kuster­ remain in the uterus and produce anatomical Hauser syndrome are usually asymptomatic ex­ amenorrhea. Pregnancy testing is negative in cept for menarchal delay, and present with nor­ these patients, and endometrial biopsy or curet­ mal somatic and sexual development. Total ab­ tage is necessary to establish the diagnosis. sence of the vagina or the presence of a small A form of endometrial refractoriness due to vaginal pouch is usually the only physical temporary involution of the endometrial glands finding. Cytogenetic studies confirm a normal may occur following discontinuation of oral contra­ 46,XX karyotype, and the basal body temperature ceptives or after the use of injectable synthetic graph is biphasic. The occurrence of normal ad­ steroids such as Depo-Provera. This form of renarche and normal female levels of serum tes­ amenorrhea, due to target-organ unresponsive­ tosterone exclude the diagnosis of congenital an­ ness, needs to be distinguished from the hypo­ drogen insensitivity