Research

The Pediatric and Adolescent Gynecology (PAG) Program and laboratory at the Eunice Kennedy Shriver National Institute of Child Health and Human Development aims to further scientific discovery involving reproductive function and health for patients aged 0 to 21. Areas of focus include:

1. Fertility Preservation with an Emphasis on Ovarian Tissue Research

Fertility preservation includes procedures used to help keep a person's ability to have children. These may give patients with cancer or other rare conditions that affect fertility the opportunity to possibly have biological children in the future, which may also improve their quality of life. Ovarian Tissue Cryopreservation (OTC) is a surgical procedure in which part, or a whole ovary is removed. The tissue, which contains immature eggs, is frozen and stored. Later in life, the tissue may be re-implanted inside the body for future fertility. In December 2019, the American Society of Reproductive Medicine Committee Opinion external link on fertility preservation in patients undergoing gonadotoxic therapies stated that OTC should be considered an established medical procedure and is no longer considered experimental. However there remain significant gaps in knowledge regarding OTC for fertility preservation in children and adolescents receiving gonadotoxic therapy as the fertility effect of gonadotoxic therapy as well as the fertility benefits of OTC cannot be ascertained until 5 to 30 years after therapy. Even less is known about OTC in patients with diminished ovarian reserve or premature ovarian insufficiency due to causes that are not due to gonadotoxic agents such as chromosomal abnormalities or genetic mutations. 

Given current gaps in knowledge and research opportunities that the advent of ovarian tissue preservation allows, our lab is addressing 3 general areas in the field of fertility preservation:

  1. Enhanced understanding of the human ovary under normal and diseased conditions, (see section on human ovary profiling)
  2. Enhanced understanding of the risks and benefits of OTC (see mouse studies 1, 2, 3)
  3. OTC for conditions associated with accelerated loss of gametes and gonadal dysfunction. (See OTC Studies)

Ovarian Tissue Cryopreservation Studies

At the NICHD-PAG, we have been involved in research through the Oncofertility Consortium external link and have been performing ovarian tissue cryopreservation (OTC) through protocols for children receiving gonadotoxic therapies (chemotherapy and radiation therapy) at Children's National Hospital since 2012. We also have two protocols that provide OTC at the NIH which also allow us to collect a small portion of ovary for research. Through these protocols we are learning about normal and abnormal human ovary structure and function as well as the possible benefit of OTC in special populations.

  1. Specific Populations Studied

    Our team focuses on the following populations:
    • Turner Syndrome
    • Classic Galactosemia
    • Adolescents with recent Premature Ovarian Insufficiency (POI)
    • Children and adolescents with autoimmune POI
    • Children and adolescents with conditions associated with POI who demonstrate diminished Ovarian Reserve
    • Variations in Sex Characteristics (VSC) or Differences of Sexual Development (DSD)
    • In addition, we provide OTC at both Children’s National and NIH for children who will receive gonadotoxic therapy (chemotherapy and radiation)
       
  2. Protocols

https://www.youtube.com/watch?v=-5yCg42nJDI external link

Publications
 

2. Human Ovary Profiling

The normal human ovary is not clearly understood as under normal healthy circumstances ovarian tissue would not be removed or biopsied. Ovarian tissue cryopreservation has allowed the opportunity to study human ovarian tissue and obtain a “snapshot” regarding histology and function. Through our ovarian tissue histology image bank and ovarian tissue biobank Thisthe PAG lab is involved in several projects that will further define ovarian histology and function.

NICHD/Oncofertility Ovarian Tissue Slide Image Databank

A digital ovarian tissue slide image database of H&E-stained ovarian and gondal tissue slides from individuals who have undergone OTC or prophylactic gonadectomy in cases of variations of sex characteristics. This digital slide database contains slides linked to clinical data from over 400 pediatric and young adult ovaries and is accessible to scientists intramurally and extramurally both nationally and internationally

NICHD Tissue Biobank

Though various OTC protocols the NICHD-PAG Lab has created an ovarian tissue biobank containing over 100 samples of pediatric and adolescent ovaries. This biobank allows us to study normal and abnormal human ovarian function.

Creating a single cell transcriptomic atlas of human ovarian tissue

Using 10X Visium spatial and single cell data, the NICHD-PAG program/lab is performing spatial transcriptomic analysis of the human ovary from early childhood to young adulthood and identifying the key regulatory network of transcription factors [REGULON] and their target genes that are responsible for primordial follicle dormancy/activation and follicular growth. This single cell and spatial transcriptomic profiling of ovarian tissue from adult donor, children, and adolescent girls with different conditions such as cancer prior to chemotherapy, prepubertal girls with galactosemia and Turner syndrome will further the understanding of molecular mechanisms leading to primary ovarian insufficiency (POI).

NICHD Ovarian Nomenclature Workshop 2021

Experts in reproductive endocrinology, gynecologic oncology, radiology, pathology, bioinformatics, and ovarian tissue research, met and created workgroups to further delineate ovarian follicle description, tissue ontology, and the 3-D description of the ovary.

Publications
 

3. Childhood and Adolescent Beginnings of Gynecologic Conditions

Endometriosis is a condition in which tissue similar to the lining of the uterus grows in other places in the body and can cause significant pain. Polycystic Ovary Syndrome (PCOS) is a set of symptoms related to a hormonal imbalance resulting in irregular periods, excessive hair growth, severe acne, infertility which can result in long term consequences including diabetes, metabolic syndrome, and uterine cancer. Lichen sclerosus is a skin condition which has been mostly studies in post-menopausal women but also affects children. All of these conditions begin during the childhood or adolescent period and are associated with significant health problems and impact quality of life. However, the study of these conditions has predominantly been done in adult populations. Pediatric and adolescent population-based studies to evaluate the beginnings of these conditions may elucidate possible early diagnosis and intervention, treatment, and prevention. The NICHD PAG Program aims to fill these gaps in research regarding the early onsets of these conditions.

Data Collection Study of Pediatric and Adolescent Gynecology Conditions

The Data Collection Study is focused on evaluating and treating gynecologic conditions including endometriosis, PCOS, and other pediatric and adolescent gynecologic conditions.

For more information, contact us at nichd-pagprotocol@nih.gov or visit Clinical Trials.

Publications
 

4. Rare Gynecologic Conditions: Implications for Human Health

The study of rare conditions often can not only help those individuals lead healthier and happy lives but can also elucidate unique physiology that affect human health and development in general. We have developed protocols to study several conditions encountered in PAG which are detailed below.

Database of Pediatric and Adolescent Gynecology Conditions

The overall purpose of this study is to provide medical and surgical management of specific PAG conditions (including Turner syndrome, congenital anomalies of the reproductive organs and premature ovarian insufficiency prior to age 21) and to gather information over time from large groups of patients within each diagnosis to help improve our understanding of these conditions.

For more information on this study, visit https://clinicalstudies.info.nih.gov/ProtocolDetails.aspx?id=2020-CH-0126.

Natural History Study of Individuals with Androgen Insensitivity Syndrome (AIS)

For more information on this study, visit https://clinicalstudies.info.nih.gov/protocoldetails.aspx?id=20-CH-0165&&query=Androgen%20Insensitivity%20Syndrome%20Natural and https://clinicaltrials.gov/ct2/show/NCT04708431.

Publications
 

5. Rare Diseases with Associated Gynecologic Conditions

Individuals with rare diseases often have significant gynecologic impact from their underlying conditions. Gynecologic conditions throughout the reproductive span in individuals with rare conditions will be evaluated in Data Collection Study of Pediatric and Adolescent Gynecology Conditions listed above.

Examples of collaboration with other NIH teams in research on gynecologic conditions in individuals with rare conditions:

  • Fibrous dysplasia/McCune Albright Syndrome (FD/MAS) - Alison Boyce, MD, NIDCR- MAS is caused by a somatic mutation that can be present in the ovary and cause spontaneous activation of ovarian function and precocious puberty. We conducted a phone interview of all women in the FD/MAS study and asked about OB/GYN history. Currently we are working with the FD/MAS investigators to evaluate bleeding and pain symptoms after menarche, obstetrical outcomes, fertility, and age of menopause.
  • Congenital Adrenal Hyperplasia (CAH) - Deborah Merke, MD, MS- Women with excess androgen conditions have significant gynecologic impact from their underlying endocrine disorder. We have conducted a case control study of sexual function and quality of life in women with CAH compared to age, race, and marital status matched controls. Based on these results we are evaluating interventional studies to improve sexual function.

Publications
 

6. Mouse Models to Study Ovarian Function and Ovarian Tissue Cryopreservation

Our lab uses mouse models to investigate ovarian function, fertility and ovarian tissue cryopreservation in conditions that mimic different human gynecologic environments. Current studies provide critical insights that inform the effects of oophorectomy as well as that of newer immunotherapy agents on fertility and reproductive health.

Effects of Oophorectomy in addition to Chemotherapy

Although women who undergo loss of one ovary appear to have a similar age of menopause as the general population, the impact of follicle loss due to oophorectomy in addition to chemotherapy is unknown. We are studying the combined effects of chemotherapy and oophorectomy (removal of an ovary) on ovarian function in mice to better understand the impact of oophorectomy on ovarian function and fertility in patients who undergo OTC followed by gonadotoxic therapy.

Oophorectomy Compensatory Project (Effects of Uni-lateral Oophorectomy or removal of one ovary on the remaining ovary)

In general population studies it has been noted that unilateral oophorectomy is associated with only a 1-2 year earlier menopause. We have noted in our previous mouse study that the ovaries in the mice that underwent unilateral oophorectomy are larger and have more follicles than the same-sided ovary in those that underwent sham surgery and hypothesize that the size of the ovary and lack of significant reduction in the age of menopause after oophorectomy is due to discernable compensatory mechanisms. This study investigates the compensatory physiological mechanisms in the remaining ovary after unilateral oophorectomy in mice. Insight into compensatory mechanisms may allow in the future for development of treatment that prolongs fertility.

CAR-T Cell Therapy

Chimeric Antigen Receptor (CAR) T-cell therapy is a promising treatment for patients with many types of blood cancer, including leukemia and lymphomas. It is a highly specialized therapy that involves genetically modifying a patient's own T cells to attack their cancer cells. Patients with CAR-T cell therapy experience immune related side effects and neurotoxicity, however, its effect on female reproductive system has not been explored. Our lab is interested in understanding the effects of CAR-T treatments on ovarian follicular development/growth in human acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) tumormouse models. These tumor mouse models will provide more insights into how the tumor micro-environment itself disrupts the ovarian follicles and whether CAR-T therapy further impacts follicular development and health.

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