Amenorrhea: A General Approach to Diagnosis and Management

1. Introduction

Primary amenorrhea is defined as the absence of secondary sexual characteristics such as growth spurt, thelarche, pubarche, and adrenarche by the age of 14; or the absence of menstruation (menarche) by the age of 16; or within 5 years of breast development (thelarche). Thelarche occurs around the age of 10.8 ± 1.1 years, and menarche occurs around the age of 12.9 ± 1.2 years [1, 2].

The Tanner classification describes the stages of thelarche and pubarche. Tanner Stage 1 corresponds to the prepubertal form, with progression to Stage 5, the full adult form, as follows:

Thelarche

Stage 1: Absence of palpable glandular breast tissue.

Stage 2: Palpable breast bud underneath the areola.

Stage 3: Palpable breast tissue beyond the areola with no areolar changes.

Stage 4: Areola forms an elevation above the contour of the rest of the breast.

Stage 5: Areola forms a single breast contour with pigmentation and nipple protrusion (Figure 1) [3, 4].

Pubarche

Stage 1: Absence of hair.

Stage 2: Downy type hair.

Stage 3: Scanty degree of terminal hair.

Stage 4: Terminal hair that fills the entire triangle overlying the pubic region.

Stage 5: Terminal hair spreads from the inguinal region to the thigh (Figure 1) [3, 4].

Fat and total body weight are relevant to puberty. Moderate obesity leads to the early onset of menarche. Physical training delays puberty by around 4 months per year of training [5].

Secondary amenorrhea is defined as no menstruation for more than 6 months in a female of reproductive age, outside of pregnancy [2].

2. Etiology

The etiology of amenorrhea could be chromosomal, genetic, enzymatic, or endocrine-related.

The most common cause of amenorrhea is gonadal dysgenesis, including Turner syndrome, followed by Müllerian agenesis (Mayer-Rokitansky-Küster Hauser syndrome), constitutional delay or chronic illness, polycystic ovary syndrome (PCOS), deficiency of gonadotropin-releasing hormone (GnRH), vaginal septum, weight loss, hypopituitarism, imperforate hymen, androgen insensitivity syndrome, hyperprolactinemia, prolactinoma, congenital adrenal hyperplasia (CAH), hypothyroidism, craniopharyngioma, and Cushing’s disease [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20].

Vaginal disorders that result in primary amenorrhea include cryptomenorrhea and transverse vaginal septum. Uterine disorders include cervical stenosis, Asherman syndrome, endometrial tuberculosis, and Müllerian agenesis [2].

Ovarian disorders that result in amenorrhea include premature ovarian failure, resistant ovarian syndrome, and PCOS. Polycystic ovary syndrome is a syndrome of ovarian dysfunction along with hyperandrogenism and polycystic ovary morphology. The prevalence of PCOS is 5–10% in general and is detected in around 25% of women undergoing ultrasound examinations for menstrual disorders [21, 22, 23].

The etiology of PCOS is unclear. It could be due to increased ovarian androgen production, disordered ovarian cytochrome p450 enzyme activity, increased production of luteinizing hormone (LH), insulin resistance, and family clusters. The clinical features of PCOS include oligomenorrhea, amenorrhea, hirsutism, subfertility, recurrent miscarriage, and acanthosis nigricans [21, 22, 23].

The main laboratory tests for PCOS are elevated testosterone levels, decreased sex hormone-binding globulin, elevated LH to follicle-stimulating hormone (FSH) ratio, increased fasting insulin levels, eight or more subcapsular cysts that are less than 10 mm in diameter, and increased ovarian stroma [21, 22, 23].

The treatment of PCOS includes weight loss, progesterone, combined oral contraception, and metformin. Troublesome hirsutism can be ameliorated by the use of eflornithine cream, cyproterone acetate, metformin, GnRH analogs with low-dose hormone replacement therapy (HRT), laser, or electrolysis. The long-term sequelae include diabetes mellitus and coronary vascular disease [21, 22, 23].

Thyroid disorders may lead to amenorrhea. Low levels of triiodothyronine and thyroxine stimulate the hypothalamus to secrete more thyrotropin-releasing hormone. Thyrotropin-releasing hormone stimulates the secretion of pituitary thyroid-stimulating hormone and prolactin. High prolactin inhibits GnRH release from the hypothalamus, leading to low levels of LH and FSH and amenorrhea. Hyperthyroidism may cause menstrual abnormalities, including amenorrhea [6].

Hypothalamic and pituitary causes include constitutional delay, Kallmann syndrome, weight loss, excessive exercise, craniopharyngioma, glioma, germinoma, dermoid cyst, head injuries, sarcoidosis, tuberculosis, infection, psychological stress, hypopituitarism, hyperprolactinemia, empty sella syndrome, and idiopathic causes [6].

Kallman syndrome leads to the deficiency of GnRH, anosmia, and hypogonadism. The syndrome was described in 1944 by Franz Joseph Kallmann, a German-American geneticist [24].

Drug-induced hyperprolactinemia can be caused by tranquilizers, tricyclic antidepressants, typical and atypical antipsychotics, narcotics, estrogen from combined oral contraceptives, medications used to treat gastroesophageal reflux disease, antihypertensives, hypnotics, and dopamine antagonists [25].

Other causes include chromosomal, genetic, enzymatic, and endocrine abnormalities. The differentiation of the gonads requires a tightly regulated cascade of genetic and molecular events that result in the appropriate phenotype corresponding to the given karyotype [16].

The basis of human development starts with the genotype 46XY, where fetuses develop into males, and the genotype 46XX develops into a female. The Y chromosome determines the gonadal development into testes. The testes-determining factor induces differentiation through the cell surface antigen found in individuals with Y chromosomes [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20].

Gonadal dysgenesis, termed streak gonad aplasia, is the defective development of gonads due to fibrous tissue formation. The result is hormonal failure and the absence of secondary sex characteristics. Causes include Turner syndrome, pure gonadal dysgenesis (PGD), mixed gonadal dysgenesis, and endocrine disruptions. Turner Syndrome is the most common cause, occurring in one in 2500 births and more frequently in abortuses.

Pure gonadal dysgenesis (PGD) could present as a 46XX or 46XY karyotype. Individuals with PGD are phenotypic females with streak gonads and normal stature. The 46XX karyotype may be autosomal recessive, resulting in nerve deafness in 10% of affected individuals [26].

The 46XY karyotype or Swyer syndrome is the mutation of the SRY gene associated with the absence of testosterone-determining factor or its receptor, failure of testicular development, no androgen or Müllerian-inhibiting factor, regression of Wolffian structure, and the persistence of Müllerian structures. Individuals with Swyer syndrome are phenotypic females with normal or excessive height as a result of delayed epiphyseal closure due to low androgens or estrogens. Menstruation occurs with estrogen therapy [27].

Androgen insensitivity syndrome, also known as testicular feminization syndrome, is an X-linked trait with absent cytosolic receptors. Affected individuals have normal breasts but no sexual hair, normal female external genitalia, an absent uterus and upper vagina, and male-range testosterone levels. Androgen insensitivity syndrome treatment includes gonadectomy after puberty and HRT, as well as vaginal dilation and vaginoplasty [28, 29, 30, 31].

Swyer syndrome patients have poor breast development, but they have a uterus and pubic hair. Treatment consists of estradiol (30–40 picograms per milliliter) and conjugated equine estrogen (0.625 milligrams) to induce breast proliferation [27].

Other causes of amenorrhea include CAH, arrhenoblastoma, 5AR deficiency, true hermaphroditism, and absence of Müllerian-inhibiting factor [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20].

Classical CAH is caused by 21-alpha hydroxylase deficiency and is autosomal recessive in 90% of cases. Patients present with decreased glucocorticoids and mineralocorticoids, increased sex hormones, hypotension, low sodium and high potassium levels, precocious puberty in males, and ambiguous genitalia in females. Treatment includes glucocorticoid therapy and corrective surgery [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20].

Late-onset nonclassical CAH is most common in 21-hydroxylase deficiency. Mild forms resemble PCOS, while severe forms show signs of severe androgen excess and high 17-hydroxyprogesterone levels. Treatment includes cortisol replacement therapy and possible corrective surgery [32].

Congenital adrenal hyperplasia with 17-alpha hydroxylase deficiency leads to decreased glucocorticoids and sex hormones and increased production of mineralocorticoids, causing hypertension, high sodium and low potassium levels. Affected females lack secondary sexual characteristics. Due to low testosterone, male patients have ambiguous or entirely female external genitalia with no development of male internal genitalia and may have undescended testes. Patients need glucocorticoid and sex HRT. Fertility requires in vitro fertilization or embryo transfer [33].

5AR deficiency is a rare genetic condition affecting sexual development in an individual with an XY genotype. Deficiency of 5AR results in the failure of testosterone to convert into dihydrotestosterone. Patients have a vagina that may be of normal or reduced size and no uterus or cervix. Treatment may be needed to enlarge the vagina. Gonads are usually in the abdomen. Treatment includes the removal of gonads and HRT needed for females [34, 35].

Penis at 12 syndromes is caused by a mutation of the 5AR type two enzyme found in the testis of individuals with an XY genotype. Patients are born with ambiguous or female external genitalia. The uterus and cervix are absent. Testes are present but remain undescended. At puberty, testosterone levels rise significantly due to 5AR type one enzyme found in the adult liver, nongenital skin, and some areas of the brain. Low 5 AR enzyme production can also contribute to testosterone production in the testes. Treatment may include removal of gonads, HRT, or assisted reproductive technology [36].

Systemic causes for amenorrhea include common debilitating illnesses, endocrine disorders, and severe weight loss. Stress from exercise can inhibit GnRH by increasing corticotropin-releasing hormone levels, which increases adrenocorticotropic hormone (ACTH), opioid peptides, and cortisol. Corticotropin-releasing hormone (CRH) also inhibits GnRH [8, 11].

Cushing’s syndrome (CS) can be either primary or secondary. Primary CS is caused by an adrenal tumor, while secondary CS is caused by ACTH hypersecretion. High CRH suppresses GnRH levels secreted by the hypothalamus. High cortisol levels lead to the suppression of steroidogenesis in the adrenal cortex, resulting in low levels of sex hormones and amenorrhea. Cushing’s syndrome is diagnosed by dexamethasone suppression test at 11 pm and serum cortisol level at 8 am the next day. Diagnosis can be confirmed with a 24-hour total urine-free cortisol measurement [37].

3. History, examination, and progesterone withdrawal test

A thorough history is vital in the management of patients with amenorrhea. It includes the nature of development, age of onset of menarche in the case of secondary amenorrhea, any chronic illnesses, weight changes, excessive exercise, anosmia, medical history, surgical procedures, menopausal symptoms such as hot flushes and night sweats, past and present medications, family history of premature and early menopause, masculinizing signs and symptoms, galactorrhea, psychological status and history, and past and present stress [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20].

The clinical examination would include height, secondary sexual characteristics that include thelarche, pubarche, and adrenarche; gynecological inspection and pelvic examination as appropriate; visual field assessment; and retinoscopy to evaluate the papilla for the presence of edema.

The first-line tests of investigating patients with amenorrhea include pregnancy tests, prolactin, thyroid function tests, LH, FSH, testosterone levels (below 5 nanomoles per liter), and a progesterone withdrawal test. Second-line investigations include chromosome analysis as required [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 38].

The progesterone withdrawal test is performed by administering medroxyprogesterone acetate, commonly known as Provera, 10 milligrams per day for 7 days, or norethisterone, also known as Aminor, 5 milligrams per day for 7 days.

If the progesterone withdrawal test is negative, an estrogen and progesterone challenge test is performed. If the test is negative, patients are prescribed estradiol at a dose of 2 milligrams per day for 3 weeks. The test should help determine the etiology, followed by karyotyping if appropriate.

An outflow abnormality should be suspected if there is no menses. On the other hand, if there is bleeding, a hypothalamic-pituitary-ovarian axis abnormality should be suspected, and FSH and LH levels should be repeated 6 weeks later. Elevated LH and FSH levels are an indication of premature ovarian failure. If hormone levels are normal, the cause is likely hypothalamic in origin (Figure 2) [38].

In conclusion, amenorrhea can be an indicator of general health and well-being. Categories of amenorrhea are varied and include ovarian, endocrine disorders, and chronic disease, in addition to enzymatic and chromosomal abnormalities. History taking should include developmental abnormalities, age of menarche, weight loss, chronic illness, exercise, medical and surgical history, anosmia, current medications, galactorrhea, menopausal symptoms, family history, virilizing signs, premature menopause, stressful events, and psychological history. Physical examination should cover anthropometric and pubertal development, pregnancy test, serum prolactin, follicle-stimulating hormone, luteinizing hormone, and thyroid function test. In addition, karyotyping, serum androgen, pelvic or brain imaging, should be performed as appropriate. Treatment of amenorrhea should be conducted according to the underlying cause and can be associated with complex pathology that may require prolonged therapy that is handled with sensitivity and emotional support.