Self-reported reproductive health in women with tuberous sclerosis complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal-dominant tumor-suppressor disorder characterized by the development of hamartomas in many organ systems. The prevalence of TSC is estimated at 1 in 6,000 individuals, and up to 70% of cases are due to de novo mutation. 1,2 Inactivating mutations in either the TSC1 or TSC2 gene, which encode the proteins hamartin and tuberin, respectively, cause TSC. 3,4 These proteins form a heterodimer involved in negative regulation of the mammalian target of rapamycin complex 1 (mTORC1) kinase. 5-7 mTORC1 is an important element in controlling cell proliferation and growth, insulin signaling, and protein translation. 8 Dysregulation of mTORC1 is an important aspect in the pathogenesis of TSC. 9 Somatic mutation of the second TSC1 or TSC2 allele leads to a loss of heterozygosity, upregulation of mTOR, and dysregulated cellular metabolism. 9 Although virtually any organ can be affected in TSC, the brain, skin, kidneys, heart, and lungs are the principal sites of pathology. TSC shows no ethnic or sex predilection, but interestingly, sex-specific manifestations have been described. Almost 40% of women with TSC develop the pulmonary manifestation lymphangioleiomyomatosis, typically between the ages of 20 and 40 years; most men are unaffected. 10,11 Moreover, the most common renal manifestation, angiomyolipoma, impacts more than 70% of patients, 2 but females are affected an estimated three to four times more often than males. 12 Lymphangioleiomyomatosis and angiomyolipomas share histological features and express estrogen and progesterone receptors, considered important in development. 13 Other effects of sex hormones or reproductive manifestations in TSC are poorly understood.Intriguingly, the role of the TSC1 and TSC2 genes in normal organ function and TSC-associated pathogenesis came to light from the creation of a variety of organ-specific Tsc1-or Tsc2-null animals. Recently, the use of conditional knockout models revealed a role for the murine Tsc1 and Tsc2 genes in the reproductive functioning of the ovary. 14,15 Specifically, these genes are crucial for the maintenance of primordial follicles in a quiescent state and appropriate activation throughout the murine reproductive period. Deletions of either the Tsc1 or Tsc2 gene in the ovaries of mice led to a premature activation of primordial follicles and subsequent depletion of the entire follicular pool, despite initial intact reproductive maturation. The mice essentially experienced what would be defined in humans as premature ovarian insufficiency (POI). POI represents a clear disruption in the normal female reproductive life span and is defined as the cessation of menses in a woman younger than 40 years. POI affects an estimated 1% of the females in the US Purpose: Little is known about sex-specific manifestations of tuberous sclerosis complex. Inactivating mutations in the TSC1 and TSC2 genes cause tuberous sclerosis complex, and recent evidence points to a crucial role for these genes in maintaining appropriate ovarian fun...

Expanding Our Knowledge of Menstrual Irregularities Reported by Females With Tuberous Sclerosis Complex

“…The rate of menstrual irregularities for the groups representing the intrinsic effects of TSC, including ( 1 ) respondents with no history of mTORi and ( 2 ) respondents with history of mTORi use—prior to initiating therapy, was 48% ( n = 24) and 49% ( n = 17), respectively. Both rates are higher than the general population rate of 5–33.5% ( 23 ) and 33% for TSC subjects indicated in previous studies ( 12 , 14 ). Furthermore, we identify that mTORi use plays an important role in the genesis of menstrual irregularities as its rate increases for subjects treated with mTORi in comparison to the non-treated group (48 vs. 74%; p = 0.001).…”

“…Another factor that might explain the differences between the studies is the average age of the cohorts as the menstrual cycle patterns and the rate of menstrual irregularities change with age. The median age was 27.5 years in our study, while the average age was 42 years in Gabitzsch et al (12) and median age was 23 years in Sparagana et al (14).…”

“…Extrapolation of cellular and animal data to the human phenotype predicts some of the reproductive abnormalities observed in TSC1 and TSC2 heterozygous females ( 12 ). Even though the mTOR pathway is a key regulator of the onset of puberty, there is no evidence of early reproductive abnormalities such as abnormal onset or timing of puberty among females with TSC ( 18 ).…”

“…After puberty, it is clinically evident that women with TSC intrinsically present with manifestations of abnormal ovarian function given the previous documentation of increased rates of menstrual irregularities, miscarriages, and infertility ( 12 , 14 ). This is further supported here in this study by the rate of menstrual irregularities in the non-mTORi group.…”

“…Similar changes in humans would present with a phenotype characterized by premature ovarian insufficiency (POI) ( 10 , 11 ). Evidence of this was supported by Gabitzsch et al who performed a cross-sectional study, revealing women with a diagnosis of TSC self-reported significant menstrual irregularities (33%), elevated rate of miscarriage (41%), and histories suggestive of several reproductive disorders ( 12 ). Another layer of complexity is the common use of mTOR inhibitors (mTORi) to reduce the size of TSC-related hamartomas across all organ systems.…”