Fig 12.1
Growth chart depicting decrease in growth velocity prior to menarche (Source: CDC 2001. Form No. 100125: Growth chart, 2–20 years, girls, stature for age, weight-for-age percentiles. http://www.cdc.gov/growthcharts)
The follicle-stimulating hormone (FSH) level is greater than 36 U/L; on repeat 4 weeks later, it is 40 U/L. A lumbar spine bone density by dual-energy X-ray absorptiometry (DXA) reveals a bone mineral density (BMD) Z-score of −2.2 SD. Her karyotype is 46,XX, and she has negative testing for FMR1 premutation and adrenal autoantibodies .
The diagnosis of primary ovarian insufficiency (POI) is made, and the patient’s mother asks you: What condition does my daughter have? What does this mean for her future health? Will I be a grandmother someday?
Discussion
POI is “the depletion or dysfunction of ovarian follicles with cessation of menses before age 40” [2]. The condition was formerly known as premature menopause or premature ovarian failure . However, ovarian function is often intermittent and unpredictable in affected adolescents and women, and ovarian reserve is decreased rather than depleted. Thus, POI is a distinct condition from premature menopause [3].
The differential diagnosis for a female patient with slowing of growth velocity prior to menarche is broad. Several conditions should be considered. Systemic illnesses such as inflammatory bowel disease and hypothyroidism, and central nervous system lesions such as craniopharyngiomas, can lead to dysfunction of the hypothalamic-pituitary axis. Various endocrinopathies, , including growth hormone deficiency and adrenal insufficiency, can also lead to slowing of growth velocity or cessation of growth entirely.
In cases where the delay in physical development is found to be due to dysfunction of the hypothalamic-pituitary-gonadal axis, the differential diagnosis includes hypogonadotropic hypogonadism and hypergonadotropic hypogonadism , which are broad categories with various subtypes (Table 12.1). In either category, patients may present with delayed puberty , delayed menarche, and/or amenorrhea.
Table 12.1
Causes of hypogonadism
Hypogonadotropic hypogonadism | Hypergonadotropic hypogonadism |
|---|---|
Isolated GnRH deficiency | Idiopathic primary ovarian insufficiency (POI) |
– Kallmann syndrome | |
– Other | |
GnRH insensitivity | Gonadal dysgenesis (e.g., Turner syndrome) |
Functional hypothalamic amenorrhea (due to disordered eating, excessive exercise, and/or psychological stress) | Ovarian insufficiency secondary to cytotoxic agents (e.g., chemotherapy) |
Brain tumor | Fragile X syndrome |
Pituitary adenomas | Autoimmune disorders |
– Isolated POI | |
– Component of autoimmune polyglandular syndrome | |
Hypopituitarism | Alcohol abuse |
Cranial irradiation or injury | Gonadal torsion |
The distinction between primary and secondary amenorrhea should be made, because this decision affects the level of suspicion for certain conditions. Patients with primary amenorrhea need to have anatomic anomalies (e.g., transverse vaginal septum, imperforate hymen) ruled out early on. Patients with secondary amenorrhea can be assumed to have typical reproductive anatomy with a patent outflow tract, and the focus should be on ruling out endocrinopathies.
POI is a form of hypergonadotropic hypogonadism : that is, the dysfunction is at the level of the ovary rather than within the hypothalamus or pituitary [4]. The diagnosis of POI is made when a female less than 40 years old has amenorrhea or menstrual irregularity for at least 3 months and has FSH levels of greater than 40 U/L on at least two occasions 1 month apart [3].
POI is associated with low levels of serum estradiol [5]. Because ovarian function tends to be intermittent, however, patients may have intermittent hypoestrogenism, with normal levels of serum estradiol at other times. Therefore, a progestin withdrawal challenge is not appropriate and may lead to delay in diagnosis, as patients with POI may have withdrawal bleeding in response to progesterone.
While most patients with POI will present with secondary amenorrhea, younger women may present with primary amenorrhea. These younger patients are more likely to have a chromosomal abnormality: approximately 50% of patients with POI who present with primary amenorrhea will have an abnormal karyotype [4].
The diagnostic workup for POI has multiple aspects including genetic testing and antibody testing for ovarian and adrenal autoantibodies [6]. However, even after a thorough evaluation, approximately 90% of cases of spontaneous POI (i.e., those not secondary to cytotoxic therapy such as chemotherapy or radiation) will remain without an identifiable cause [5].
At the time of diagnosis, patients may already have encountered the effects of intermittent hypoestrogenism . These include temporary, reversible effects such as vaginal dryness and hot flashes, which often will completely resolve with hormone replacement therapy. On the other hand, the effects of low serum estradiol on bone density may not be as easily reversed. When patients are diagnosed with POI in adolescence, this is an even more significant issue, as adolescence (up to age 19) is the time of peak accumulation of bone mass for women.
Thus, an important component of the initial evaluation for POI is the measurement of bone density, obtained via DXA. Patients should have a DXA BMD measurement of the lumbar spine as early as possible in their workup (Fig. 12.2). The spine is rich in metabolically active trabecular bone and is typically the first site to exhibit skeletal losses. This measurement will help guide initial medical therapy, including hormone replacement, as well as calcium and vitamin D supplementation. As the variance in an individual’s bone density is 70–80% predicted by genetic factors, it can be helpful to obtain a baseline bone density by DXA as an initial assessment of bone health.
