A clinical research integration special program (CRISP) for young women with primary ovarian insufficiency

Abstract

Large-scale medical sequencing provides a focal point around which to reorganize health care and health care research. Mobile health (mHealth) is also currently undergoing explosive growth and could be another innovation that will change the face of future health care. We are employing primary ovarian insufficiency (POI) as a model rare condition to explore the intersection of these potentials. As both sequencing capabilities and our ability to intepret this information improve, sequencing for medical purposes will play an increasing role in health care beyond basic research: it will help guide the delivery of care to patients. POI is a serious chronic disorder and syndrome characterized by hypergonadotrophic hypogonadism before the age of 40 years and most commonly presents with amenorrhea. It may have adverse health effects that become fully evident years after the initial diagnosis. The condition is most commonly viewed as one of infertility, however, it may also be associated with adverse long-term outcomes related to inadequate bone mineral density, increased risk of cardiovascular disease, adrenal insufficiency, hypothyroidism and, if pregnancy ensues, having a child with Fragile X Syndrome. There may also be adverse outcomes related to increased rates of anxiety and depression. POI is also a rare disease, and accordingly, presents special challenges. Too often advances in research are not effectively integrated into community care at the point of service for those with rare diseases. There is a need to connect community health providers in real time with investigators who have the requisite knowledge and expertise to help manage the rare disease and to conduct ongoing research. Here we review the pathophysiology and management of POI and propose the development of an international Clinical Research Integration Special Program (CRISP) for the condition.

Figure 1

Transvaginal ultrasound scan from a patient with spontaneous 46,XX primary ovarian insufficiency who had follicle dysfunction due to autoimmune oophoritis. Many developing follicles are visible [From Nelson LM].

Figure 2

Ovarian histology in a biopsy proven case of autoimmune oophoritis. Hematoxylin and eosin staining shows multiple antral follicles in patient 1 (A), bar = 1 cm. Higher magnification shows lymphocytic infiltration of the theca of an antral follicle and luteinized granulosa cells (B), bar = 50 μm. Immunoperoxidase staining for CD3 highlights infiltration of lymphocytes into the theca in this patient (C), bar = 500 μm. Immunoperoxidase staining for CD3 demonstrates infiltration of lymphocytes into the theca of a preantral follicle in patient 4 and presence of earlier stage follicles free of lymphocytic infiltration (arrows) (D), bar = 100 μm. [From Bakalov VK et al.].

Figure 3

Schematic representation of pathophysiology of SCA-POI. The selective autoimmune destruction of theca cells with preservation of granulosa cells is responsible for a reduced production of oestradiol because of lack of substrates. The subsequent increase in FSH levels would stimulate viable granulosa cells that, in return, would produce increased amounts of inhibins.