Introduction
Puberty is defined as the acquisition of adult height, bone strength, sexual characteristics, and reproductive capacity. Female puberty is divided between multiple stages, the first of which is thelarche (breast budding). Thelarche typically occurs after 8 years of age and is followed by pubarche (pubic hair development), a growth spurt, and finally, menarche. Menarche occurs 2 to 3 years after thelarche, with the average age of onset at 12.4 years. The determinants of menarcheal age are undergoing continuous study; however, research has shown that socioeconomic status, genetics, general health, nutrition, and exercise appear to play a role. (See Chapter 5 on puberty for more information.)
Amenorrhea, or the absence of menses, may be either a transient or permanent phenomenon caused by disruption at any point in the hypothalamic-pituitary-gonadal (HPG) axis or female reproductive system. Amenorrhea is classified as either primary or secondary. Primary amenorrhea is defined as the absence of menarche in ≥15-year-old females with or without developed secondary sexual characteristics and normal growth or if there is a lack of menses 3 years after thelarche. Secondary amenorrhea is defined as the absence of menses for 6 months or the equivalent of three previous cycle intervals, whichever is longer, in adolescents who previously had menses. The epidemiology, evaluation, and management of common causes of primary and secondary amenorrhea will be discussed in this chapter. Remember that some etiologies can present as either primary or secondary amenorrhea.
Primary amennorhea
The initial workup for a patient with primary amenorrhea is going to rely on the history and physical examination, specifically the absence or presence of secondary sexual characteristics ( Fig. 11.1 ). This assessment will lead to laboratory work to assess for gonadotropin rise or evaluation of androgen levels, which may then lead to further laboratory work and/or pelvic ultrasounds ( Table 11.1 ). Treatment will then be dependent on the diagnosis reached, but may involve estrogen replacement, caloric balancing, or surgical consultation.
| Anatomic Site | Etiology | Signs and Symptoms | Laboratory Findings | Imaging Findings | Karyotype |
|---|---|---|---|---|---|
| Hypothalamus | Kallmann syndrome | Anosmia, hearing loss, cleft lip/palate, synkinesis, unilateral renal agenesis, absent secondary sexual characteristics | Prepubertal low levels of LH and FSH, negative progesterone challenge, positive estrogen/progesterone challenge | No abnormalities | 46,XX |
| Ovary | Turner syndrome | Short stature, webbed neck, widely spaced nipples, horseshoe kidney, streak ovaries | Elevated FSH and LH levels; low AMH and estradiol | Streak gonads on pelvic ultrasound | 45,XO, can be mosaic 45,XO/46,XX, 45,XO/46,XY, or more rare X chromosome mosaics |
| Swyer syndrome | Tall stature, functional female genitalia and structures, streak ovaries | Elevated FSH and LH levels, low estradiol levels | 46,XY | ||
| Uterus | Müllerian agenesis (Mayer-Rokitansky- Küster-Hauser syndrome) | Typical female secondary sexual characteristics, short and blind-ended vagina | Normal LH, FSH, and testosterone levels | Small or absent uterus with ovaries present on pelvic ultrasound | 46,XX |
| Androgen insensitivity syndrome | Absence of the upper vagina, uterus, and fallopian tubes; testes may be palpable in the labia or inguinal area; sparse pubic and axillary hair | Normal or elevated LH, elevated testosterone | Abdominal or inguinal gonads on ultrasound or MRI | 46,XY | |
| Vagina | Transverse septum | Cyclic pelvic pain, possible vaginal or pelvic mass, typical secondary sexual characteristics | Normal laboratory tests | May be noted as hypointense on pelvic MRI | 46,XX |
| Hymen | Imperforate hymen | Cyclic pelvic pain, hematocolpos, typical secondary sexual characteristics | Normal laboratory tests | Rarely indicated | 46,XX |
| Miscellaneous | Constitutional delay of growth and puberty | Delayed adrenarche and gonadarche, family history of “late bloomers” | Lower levels of LH and FSH, delayed bone age | Normal except delayed bone age | 46,XX |
| 5-Alpha reductase deficiency | Ambiguous genitalia at birth, virilization during puberty | Elevated serum testosterone-to-DHT ratio | Abdominal or inguinal gonads on ultrasound or MRI | 46,XY |
Turner syndrome
Turner syndrome is the most common cause of primary amenorrhea and occurs in approximately 1/2000 females. In the most common form of Turner syndrome, the X chromosome is missing completely, and individuals have a 45,XO karyotype (40%–50% of cases). Turner mosaicism also exists in which there is a cell line with X monosomy and another with 46,XX (45,XO/46,XX; 15%–25% prevalence), a 46,XY cell line (45,XO/46,XY; 10%–12%), or a cell line with three X chromosomes (3%). Of note, the genotype does not correlate with the severity of the phenotype.
Common associated phenotypic features, pictured in Fig. 11.2 and 11.3 , include short stature, a webbed neck, low hairline, broad “shield” chest, congenital heart disease (bicuspid aortic valve, aortic coarctation), horseshoe kidney, and primary ovarian insufficiency (POI). In Turner syndrome, ovarian oocytes and follicles undergo accelerated apoptosis, often in utero, and are eventually replaced by fibrous tissue. This results in lack of sufficient oocytes for menses by puberty, streak ovaries on ultrasound ( Fig. 11.4 ), and early menopause.
In Turner syndrome, the external female genitalia, uterus, and fallopian tubes develop normally until puberty, when estrogen-induced maturation fails to occur because of the absence of ovarian follicles. Such individuals may lack secondary sexual characteristics, such as breast development, but should still progress normally through adrenarche (i.e., development of pubic hair, skin oiliness/acne, and body odor). There are some individuals who achieve menarche or spontaneous puberty with ovarian insufficiency by menarche.
Patients with suspected Turner syndrome based on history and examination should undergo a karyotype analysis. Other laboratory studies will show significantly elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels because of the absence of ovarian oocytes and follicles. Anti-müllerian hormone may also be used as a marker for ovarian insufficiency and would be extremely low or undetectable. , Once the diagnosis is confirmed, all patients should also undergo a complete cardiac evaluation to evaluate for structural abnormalities.
Treatment of Turner syndrome focuses on hormonal therapy. Patients may receive growth hormone and estrogen to improve growth outcome, uterine length and volume, bone mineralization, and peak bone mass. Given the risk for short stature, patients with Turner syndrome will be offered growth hormone, even if identified at a pubertal age, to attempt to optimize growth before initiation of pubertal estrogen to maximize linear growth before growth plate closure but estrogen replacement for those identified younger may start early at a low dose to also help optimize height attainment. , (See Chapter 18 on POI/Turner syndrome for more information.)
Swyer syndrome
Swyer syndrome, or 46,XY gonadal dysgenesis, is significantly less common than Turner syndrome and occurs in approximately 1/100,000 births. In complete 46,XY gonadal dysgenesis, the fibrous streak gonads resemble ovarian tissue but cannot secrete anti-müllerian hormone, resulting in persistent müllerian structures and a female phenotype. Individuals are born with functional female genitalia and structures, including a vagina, uterus, and fallopian tubes. Patients often present during adolescence or early adulthood with lack of pubertal development or primary amenorrhea, although adrenarche and stature are normal.
The presentation of Swyer syndrome and Turner syndrome can be similar, but there are phenotypic differences as well as the genetic differences ( Table 11.2 ). If Swyer syndrome is suspected based on examination and history, the patient should undergo a karyotype analysis and laboratory tests for FSH, LH, prolactin, thyroid-stimulating hormone (TSH), free thyroxine (T 4 ), androstenedione, estradiol, and testosterone. FSH and LH levels will be elevated with low estradiol levels, suggestive of hypergonadotropic hypogonadism. Swyer syndrome patients will also have low androgen levels.
| Turner Syndrome | Swyer Syndrome |
|---|---|
|
|
Treatment for Swyer syndrome involves hormonal replacement therapy with estrogen and progesterone from puberty onward. In addition to helping with the development of secondary sexual characteristics, hormone replacement therapy can also assist in the prevention of bone loss and osteoporosis. Completely undeveloped streak gonads (see Fig. 11.4 ) are associated with an increased risk of abdominal tumors (most commonly dysgerminoma), so a gonadectomy is recommended at the time of diagnosis.
Mayer-Rokitansky-Küster-Hauser syndrome
Mayer-Rokitansky-Küster-Hauser syndrome, or müllerian agenesis, occurs in approximately 1/5000 adolescents. Due to the failure of müllerian duct development, females with a 46,XX karyotype undergo agenesis of the uterus and upper two-thirds of the vagina. Because these individuals have functional ovaries, secondary sexual characteristics develop normally and external genitalia are typical female but the vagina is short and blind-ended.
Patients typically present with primary amenorrhea despite normal secondary sexual characteristics. Laboratory findings include normal LH, FSH, and testosterone levels. A chromosome analysis can be performed to rule out Turner syndrome and androgen insensitivity syndrome. Abdominal or translabial imaging can be performed to assess for the presence of a midline uterus. Magnetic resonance imaging (MRI) will demonstrate rudimentary müllerian structures in a majority of patients with müllerian agenesis.
Treatment includes vaginal and surgical care. Vaginal agenesis is treated by noninvasive vaginal dilatation (first-line therapy) or vaginoplasty. , Genetic motherhood is possible by using gestational surrogacy. (See Chapter 26 on nonobstructive müllerian anomalies for more information).
Complete androgen insensitivity syndrome
This is an X-linked recessive disorder that affects 2 to 5 per 100,000 individuals who are genetically male. 46,XY patients with this disease will appear to have a normal external female phenotype. Due to a defect in the androgen receptor, patients fail to develop all of the male sexual characteristics that are dependent on testosterone. Their external genitalia are typically female in appearance, but testes may be palpable in the labia or inguinal area. This is because their testes make müllerian-inhibiting substance, causing regression of all müllerian structures (fallopian tubes, uterus, and upper third of the vagina). At puberty, breast development occurs, but pubic and axillary hair are sparse.
Diagnosis is based on the absence of the upper vagina, uterus, and fallopian tubes on physical examination and pelvic ultrasonography, high serum testosterone concentrations (in the range for normal men), and a male (46,XY) karyotype.
Treatment involves surgical excision of the testes after puberty if located intraabdominally because of the increased risk (2%–5%) of developing testicular cancer after 25 years of age.
Constitutional delay of growth and puberty
Constitutional delay is the most common cause of delayed puberty and menarche in girls, comprising up to ∼30% of females with primary amenorrhea. Characterized by both delayed adrenarche and gonadarche, it is often difficult to distinguish clinically from congenital gonadotropin-releasing hormone (GnRH) deficiency.
Constitutional delay of growth and puberty is a diagnosis of exclusion, and one must first rule out hormonal deficiencies, systemic illness, or syndromes associated with growth impairment. Laboratory workup should include other causes of short stature and amenorrhea, including TSH, T 4 , insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGF-BP-3), karyotype, and the growth hormone (GH) stimulation test, which would all be expected to be in the normal range. Low levels of LH and FSH are expected in adolescents with younger skeletal age caused by physiologic hypogonadotropic hypogonadism. Bone age is usually delayed compared with chronologic age, but the developmental milestones are achieved at usual bone ages. Parents or siblings may give a history of being “late bloomers,” with a late growth spurt or late puberty compared with their peers.
There is no treatment for constitutional growth delay other than reassurance and monitoring. These individuals will eventually progress through spontaneous puberty and menarche and do not require treatment.
Kallmann syndrome
Kallmann syndrome, or isolated GnRH deficiency with anosmia, occurs in approximately 1/125,000 females. This condition develops because of the lack of migration of gonadotropes in the hypothalamus through the olfactory node. Approximately 50% of patients have a demonstrable genetic mutation that is identifiable but occurs in multiple genes. Because of the absence of hypothalamic GnRH, laboratory findings are notable for pulsatile and prepubertal low serum gonadotropin concentrations (LH, FSH).
Secondary sexual characteristics are often completely absent, and adolescents will have an inability to smell. Associated congenital anomalies include midline defects (cleft lip/palate), neurosensory hearing loss, synkinesis (alternating mirror movements), unilateral renal agenesis, and skeletal defects including syndactyly and ectrodactyly (lobster claw deformity).
Diagnosis is made via hormone evaluation, olfactory function testing, and imaging such as MRI of the brain to evaluate the olfactory bulbs. Patients will also have a negative progesterone challenge test if an attempt to invoke menses is undertaken. This test involves administration of medroxyprogesterone, which leads to secretory transformation of the endometrium and withdrawal bleeding within a week of finishing the medroxyprogesterone course. Adolescents with a profound decrease in estrogen who lack an estrogen-primed endometrium, including patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism, are unlikely to respond. This is in contrast to administration of estrogen followed by medroxyprogesterone, which is typically followed by withdrawal bleeding in most adolescents with amenorrhea secondary to hypogonadism, including Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. A lack of withdrawal bleeding with administration of estrogen and medroxyprogesterone suggests the presence of abnormal endometrium (including uterine synechiae) or outflow obstruction.
Treatment for Kallmann syndrome involves hormone replacement therapy with exogenous GnRH administered in a pulsatile regimen designed to mimic endogenous GnRH secretion.
5-alpha reductase deficiency
This is a rare autosomal recessive disorder occurring in genetic 46,XY males and is also known as huevos a las doce based on a Dominican community with high incidence. In this community, these individuals are recognized as having their own gender. These patients have bilateral testes and normal testosterone production, but they have impaired virilization during embryogenesis caused by an inability to convert testosterone via 5-alpha reductase to its more potent metabolite, dihydrotestosterone (DHT). As a result, at birth, these neonates may appear phenotypically female or have ambiguous genitalia. Later during puberty, the disorder is more recognizable because of the onset of virilization (male-pattern hair growth, increased muscle mass, and voice deepening) caused by the normal peripubertal increase in testosterone secretion in males. These individuals do not undergo DHT-dependent masculinization (enlargement of the male external genitalia and prostate).
Diagnosis is typically made in the newborn period when neonates present with ambiguous genitalia. These individuals may also present during puberty with clear signs of virilization. Laboratory evaluation includes a karyotype, 17-hydroxyprogesterone, FSH, LH, testosterone, DHT, anti-müllerian hormone, electrolytes, and urinalysis. Elevated serum testosterone-to-DHT ratio is the hallmark of 5-alpha reductase deficiency. An abdominopelvic ultrasound should also be obtained to assess for the presence of internal male/female structures.
Treatment includes a multidisciplinary discussion regarding the long-term effects of gender assignment, including gender identity, gender role, and sexuality. In patients with 5-alpha reductase deficiency who are raised as male, testosterone or DHT therapy may increase penile length. If testosterone is used in a prepubertal patient for a prolonged course, parents should be counseled over the possibility of decreasing final adult height secondary to androgen-associated skeletal advancement. In such patients who are raised female, estrogen replacement therapy may be started at a bone age of 12 years or once an increase in gonadotropins is observed. Cycling of estrogen therapy or progesterone is not required because of the lack of a uterus.
Anatomic causes of primary amenorrhea
Imperforate hymen
The incidence of an imperforate hymen is estimated to be 1 in 1000 female births. Patients may present with cyclic pelvic pain and a bulging, blue-colored mass caused by the retained blood in the vagina, referred to as a hematocolpos . This is diagnosed with a physical examination and easily corrected with surgery.
Transverse vaginal septum
The incidence of transverse vaginal septum is estimated to be 1 in every 70,000 females. This condition occurs because of the failed fusion of the vaginal plate and the urogenital sinus.
After menarche, symptoms are similar to those associated with an imperforate hymen, with cyclic pelvic pain and possible vaginal or pelvic mass, but this may depend on the location of the septum (transverse vs. longitudinal). Laboratory findings are normal, and patients will develop typical secondary sexual characteristics and undergo typical puberty and adrenarche, but present with amenorrhea or dysmenorrhea. Diagnosis is by physical examination, and management is surgical. (See Chapter 27 on obstructive müllerian anomalies for more information.)
Secondary amenorrhea
The initial workup for a patient with secondary amenorrhea will also rely on the history and physical examination in addition to a need for confirmatory laboratory work with gonadotropin levels, thyroid function monitoring, and pituitary function screening, which may then lead to further workup with imaging ( Fig. 11.5 , Table 11.3 ). Treatment will then be dependent on the diagnosis reached.
