Introduction
Primary ovarian insufficiency (POI) refers to the decline of ovarian function before age 40 years. Also known as hypergonadotropic hypogonadism, POI has previously been referred to as premature ovarian failure or premature menopause. It can manifest at variable developmental stages, from early childhood through adulthood. Postmenarchal individuals experience oligomenorrhea or amenorrhea for ≥4 months in conjunction with elevations in follicle-stimulating hormone (FSH). However, normal variations in the length of menstruals cycle during early adolescence can lead to a delay in diagnosis. 
Early detection and a low threshold for clinical suspicion are essential. Once POI has been diagnosed, it is important to determine the etiology and begin appropriate evaluations, referrals, and management to properly counsel the patient and family. ,
Disease
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Primary ovarian insufficiency
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Turner syndrome (TS)
Definition
Primary ovarian insufficiency:
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Oligomenorrhea/amenorrhea for at least 3–4 months
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Elevated FSH >25 IU/L on two occasions 1 month apart
Turner syndrome:
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Missing or structurally altered X chromosome and one or more typical clinical manifestations affecting development, growth, or multiple organ systems
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Missing X-chromosome material can occur in all cells (monosomic TS) or a percentage of cells (mosaic TS)
Prevalence and epidemiology
Primary ovarian insufficiency:
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0.01% <20 years old
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0.1% <30 years
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1% <40 years
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Factors affecting age at natural menopause:
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Ethnicity: The prevalence of POI in the United States is higher in Black and Hispanic women compared with White women and lower in women with Chinese and Japanese ancestry. ,6
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Lifestyle: Smoking is a risk factor for earlier onset of menopause.
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Socioeconomic factors: Higher socioeconomic status was associated with later onset of menopause. Lower cognitive scores in childhood were associated with earlier menopause.
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Turner syndrome:
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Prevalence: 1/2000 to 2500 ,
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Epidemiology: Median age of diagnosis is 15.1 years
Etiology and pathophysiology
POI consists of a continuum of diminishing ovarian function associated with elevated FSH and decreased anti-müllerian hormone (AMH) levels. The etiology includes autoimmune disease, infectious causes, exposure to radiation and chemotherapy, and genetic causes including chromosome abnormalities and a growing list of single-gene disorders ( Table 18.1 ). However, the majority (75%–90%) of POI remains idiopathic.
| Category | Diagnosis |
|---|---|
| Genetic Causes |
|
| Autoimmune |
|
| Infectious |
|
| Iatrogenic |
|
| Environmental |
|
AMH levels increase in an inconsistent manner during adolescence and reach their highest point in the early 20s. As a result, interpreting serum AMH levels in adolescents can be challenging. Additionally, AMH levels are typically suppressed during chemotherapy, rendering them less useful in individuals receiving treatment. Lastly, although an ultrasound can directly measure antral follicles (2–10 mm), there are no established normal ranges for this measurement in adolescents ( Fig. 18.1 ).
Manifestations of disease
Primary ovarian insufficiency
Individuals present with delayed puberty, primary or secondary amenorrhea, irregular menses ≥4 months apart, infertility, vasomotor symptoms (hot flashes, night sweats), vaginal dryness, or mood changes. Intermittent remission and return of ovarian function can occur in 5%–10% of cases. ,
Long-term manifestations include:
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Lack of development of secondary sexual characteristics
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Metabolic disorders
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Osteopenia/osteoporosis
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Cardiovascular disease
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Infertility
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Vulvovaginal atrophy
Turner syndrome
In individuals with TS, it is also important to consider the following clinical manifestations:
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Growth failure (short stature)
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Congenital heart anomalies
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Hypertension
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Thyroid dysfunction
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Impaired glucose function
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Hyperlipidemia
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Celiac disease
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Hearing loss
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Strabismus, nearsightedness, ptosis
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Dental complications
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Renal anomaly (e.g., horseshoe kidney)
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Neuropsychological/behavioral issues (anxiety, nonverbal learning difficulty)
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Skeletal abnormalities
Recommended referrals for patients with TS include pediatric endocrinology, pediatric cardiology, pediatric and adolescent gynecology (with expertise in fertility preservation), genetics, psychology, audiology, ophthalmology, and dentistry.
Clinical presentation and evaluation
Very young children with TS may present with short stature ( Table 18.2 ). Older children and adolescents with POI present with delayed or arrested pubertal development and primary or secondary amenorrhea. Young adults may present with infertility, hot flashes, night sweats, vaginal dryness, and dyspareunia.
