Bone Health in Primary Ovarian Insufficiency

Rose Marino, M.D.; Madhusmita Misra, M.D., M.P.H.

Disclosures

Semin Reprod Med. 2011;29(4):317-327. 

In This Article

Abstract and Introduction

Abstract

The etiology of primary ovarian insufficiency (POI) may be genetic, autoimmune, or iatrogenic. Genetic conditions include 45,X, 46,XX and 46,XY POI, and POI associated with galactosemia and FMR premutations. Women with autoimmune polyglandular syndromes 1 and 2 may develop autoimmune POI, as may those who receive chemotherapy or radiotherapy. Hypogonadism in POI can result in reduced rates of bone mass accrual in adolescents and young women, and low bone density for age in older women. Measures to optimize bone density in women with POI include attention to lifestyle measures and hormone replacement. Resistance training and adequate calcium and vitamin D supplementation are essential, as is replacement of estrogen/progestin. Estrogen/progestin replacement may be problematic in women with estrogen-sensitive breast cancer who developed POI in the course of therapy for cancer. In these instances, bisphosphonates are an option. In particular, zoledronic acid has been used successfully in conjunction with chemotherapy, tamoxifen, and aromatase inhibitors.

Introduction

Primary ovarian insufficiency (POI) is defined as ≥4 months of oligoamenorrhea in a woman <40 years old, associated with at least two follicle-stimulating hormone (FSH) levels in the menopausal range, obtained more than a month apart.[1] This is a state of hypergonadotropic hypogonadism, and similar to other hypogonadal states, it has been associated with low bone density. Spontaneous POI can result from chromosomal abnormalities, as in Turner's syndrome and other forms of X chromosome-associated ovarian insufficiency (45X, 45X/46XY, 45X/46XX). More commonly, this is associated with a 46,XX karyotype and may be either syndromic or nonsyndromic (described in Nelson[1]). Some syndromic causes of 46,XX POI include fragile X-associated disorders (abnormal numbers of CGG repeats in FMR1), autoimmune polyendocrine syndromes types 1 and 2, 17α hydroxylase deficiency, lipoid adrenal hyperplasia, aromatase deficiency, galactosemia, Fanconi's anemia, ataxia-telangiectasia, Bloom's syndrome, Werner's syndrome, and mutations in FOXL2 and POLG. POI can also result from iatrogenic causes including use of chemotherapeutic agents (particularly alkylating agents) and exposure to radiation. A discussion of all causes of POI is beyond the scope of this review, but some specific conditions are reviewed in the context of their impact on bone health.

The ovaries secrete both estrogen and testosterone, hormones that have an important role in establishing and preserving bone health. At pubertal onset, rising levels of estrogen stimulate an increase in growth hormone (GH) and insulin-like growth factor (IGF)1 secretion, both of which are bone trophic hormones. GH, both directly and through IGF-1, stimulates osteoblastic activity, and studies also indicate a direct effect of GH on osteoclasts.[2] Rising levels of estrogen in puberty have an inhibitory effect on osteoclastic activity and reduce endosteal bone resorption. The combined effects of GH, IGF-1, and estrogen result in a marked increase in bone mass in the pubertal years, and, in fact, >90% of peak bone mass is achieved by 18 years of life.[3] There are concerns that impaired bone accrual in the adolescent years may lead to permanent deficits in peak bone mass and that untreated hypogonadism in the teenage years may lead to long-term deficits that are more severe than when hypogonadism occurs in later life. In addition, the ovaries secrete testosterone, which has an anabolic effect on bone, and is also aromitized to estrogen and low testosterone in women has also been associated with low bone density.[4]

POI is associated with deficits in estrogen and testosterone secretion, and thus an impact on bone density is to be expected. Although POI is more commonly seen in adult women, 10% of those with spontaneous 46,XX POI present in adolescence with primary amenorrhea.[1] These teenagers are at some risk for significant bone deficits, particularly if diagnosis is delayed or if treatment is suboptimal. In adult life, estrogen is necessary for maintenance of bone density, and therefore, POI in adults is also of concern.

Importantly, unlike in menopause and many other conditions of hypogonadism, ovarian function in about half of all women who have POI is variable and can be quite unpredictable. In fact, 5 to 10% of women diagnosed with POI eventually conceive.[1] Therefore, estrogen deficiency may be intermittent and less profound in POI than in other causes of hypogonadism.

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