Matthew Poling (mpoling@ucsd.edu)

Graduate Program:  Biomedical Sciences
Lab PI: Alexander S. Kauffman, Ph.D.
Undergraduate Institution: UC San Diego
Med-into-Grad Clinical training area: Reproductive Medicine
Main clinical mentor:
R. Jeffery Chang, M.D   rjchang@ucsd.edu
Kevin Mass, M.D./Ph.D.   k1maas@ucsd.edu
Sanjay Agarwal, M.D.   skagarwal@ucsd.edu
H. Irene Su, M.D. MSCE   hisu@ucsd.edu

Rational for Med-into-Grad training:
     My thesis research focuses on the neuroendocrine control of reproduction during development (puberty) as well as in adulthood. My research focuses on two related neuropeptides, kisspeptin and RFamide-related peptide 3 (RFRP-3), which have opposite effects on the secretion of gonadotropin-releasing hormone (GnRH). The pattern of GnRH on the pituitary dictates which gonadotropin, luteinizing hormone or follicle-stimulating hormone, is released. Therefore, understanding the control of GnRH release is important for understanding the pattern in which gonadotropins are secreted and act on the gonad to produce sex steroids. Taking a step back, I am examining the development of both kisspeptin and RFRP-3 in a mouse model to understand how these neuropeptide systems change during development to allow for pubertal reproductive transition. More specifically, I am examining the role of RFRP-3 in energy balance, as body weight and the current nutritional status are permissive factors for pubertal progression.

Medical training and identification of medically-relevant research issues: 
The clinical training I received was in reproductive endocrinology and infertility. This subspecialty is focused on how hormonal changes regulate the reproductive system and the pathologies that are associated. One of the most common patient complaints that bring them into this clinic is infertility. I observed the diagnostic process to determine the cause of infertility as well as determining a therapeutic plan short of in-vitro fertilization. I was able to observe the follicular development via ultrasound in these patients during ovulation induction, and then eventual intra-uterine insemination after triggering ovulation. I was also able to observe aspects of in-vitro fertilization, which begins with ovulation induction, but then includes oocyte retrieval, sperm co-culturing/intracytoplasmic sperm injection, and embryo culture. Separately, but often indicated with infertility, I also observed the management of patients with polycystic ovarian syndrome, endometriosis, and premature ovarian failure due to chemotherapy. While these patients may not be actively trying to conceive, reproductive endocrinologist mange their condition pharmacologically.

With respect to research, there are several conditions that are poorly understood, and several therapies that could be improved. Recurrent pregnancy loss is a physically and emotionally devastating condition that is poorly understood and has very few therapies. This diagnosis is largely a catchall term for a variety of anatomical, chromosomal, endocrine, immune, and reproductive pathologies. Determining the exact etiology of the condition in a couple is often difficult and even when the source is found, there is often very little a physician can provide in terms of therapy. Recurrent pregnancy loss is difficult to study clinically due to the delicate nature of early pregnancy, and difficult to study as basic scientists to due a lack of good animal models. Furthermore, since the cause can be from a variety of sources, a therapy that may prove useful for one cohort of patients may have no effect in others, despite having the same initial problem, frequent miscarriages.

Another area of clinical research that requires further research is the origin of polycystic ovarian syndrome (PCOS). While this disease has been extensively studied, there is still no consensus on what the origin of the disease is or how to accurately diagnosis it. Having polycystic ovaries by ultrasound does not necessarily indicate that a patient has the various endocrine abnormalities associated with polycystic ovarian syndrome, and the various endocrine abnormalities may not be present with polycystic ovaries. These discrepancies make the assessment as to the efficacy of treatments and the pathophysiology of the disease difficult to study. An interesting observation that has been made clinically is that the polycystic ovary phenotype is actually present in a fair majority of adolescent girls, suggesting that a polycystic/multifollicular ovary is a part of normal sexual development. Therefore, the development of PCOS in adulthood may stem from an inability for the ovarian pubertal transition to be completed. This is something that could be examined both clinically and by basic scientist.

Potential Research collaborations:
A collaborative project that could be completed between our laboratory and the clinic are experiments examining the developmental etiology of PCOS. If a polycystic ovary is form of ovarian neoteny, as the polycytic ovary is observed more frequently in adolescent girls than the general adult population, then interfering with normal pubertal changes at the hypothalamic level may lead to a PCOS phenotype in adulthood. Using animal models, we could expose rodents to various hypothalamic receptor agonists and antagonists during the pubertal transition, and then examine the rodents in adulthood for a PCOS-like effect. Similarly, experiments are already being done clinically to examine adolescent girls with and without PCOS to determine 1) if the polycystic ovary is indicative of their endocrine condition, 2) what factors maybe regulating or triggering these pathological endocrine responses. It is unclear if I would personally be partaking in these experiments.

Circulating levels of Anti-Müllerian hormone (AMH) are reflective current ovarian reserve, and physicians can measure this hormone to determine if a patient is undergoing premature ovarian failure. The function of AMH is unknown. What does AMH do in normal adult physiology? Is this something that can be therapeutically exploited? Trying to understand what this hormone does can be determined in a basic science lab. Cell culture systems could be used to determine how AMH signals in ovarian cells. Knockout mice can be used to determine the necessity of AMH in adult female reproductive physiology, and normal mice can be used to determine how AMH expression changes throughout life and during folliculogenesis. Based on these results, AMH could be given to patients in a phase II clinical trial setting to determine it’s effects as a therapeutic agent. This is a bit separated from my current research projects; therefore I would not be conducting these studies.

Training in diagnostics & therapeutics, and identification of unmet diagnostic & therapeutic needs:
I have been able to observe many diagnostics and therapeutics related to reproductive medicine, including in-vitro fertilization, and I feel like this has been a good representation of current infertility medicine. I have able been able to observe transvaginal ultrasounds, saline-infusion sonograms, ultrasound guided oocyte retrieval and several aspects of in-vitro fertilization. These are the gold standards of infertility diagnostics and treatment.

I believe that there is need for a better way to visualize follicle development without using transvaginal ultrasound. While patients do not generally complain about this procedure, an abdominal ultrasound is considerably less invasive. This is outside my expertise and I have no idea how to create better ultrasound of non-invasive monitoring systems. Aside from this diagnostic need, there is also need for better drugs that can manipulate gonadotropin secretion. While giving exogenous gonadotropins are effective in promoting follicle development, these recombinant drugs are expensive and require daily injections. As most infertility treatments are out-of-pocket, the difference in cost can be a major factor in the success of their infertility treatment. The development of oral new selective estrogen receptor modulators (SERM) or SERM like drugs would prove useful in inducing greater gonadotropin release. SERMs act in the hypothalamus, and kisspeptin neurons are a known population of estrogen responsive cells that are essential for fertility. Therefore, finding ways to increase kisspeptin secretion by modulating estrogen response would likely prove useful for increase subsequent gonadotropin secretion. There is need for better diagnostics and therapeutic courses for recurrent pregnancy loss. There is currently very little that can be done determine the cause of their infertility, since they do become pregnant and most diagnostics are examining at preconception conditions. Trying to clinically examine the known causes of this condition blindly is often unproductive and not cost effective. Additionally, there are few therapies for recurrent pregnancy loss for the same reason as the limited diagnostics; becoming pregnant isn’t the issue, it’s continuing to carry the pregnancy. Little has been done in this field due to the variety of origins for recurrent pregnancy loss as well as the difficulty in studying early maternal-fetal interactions.

Diagnostic & Therapeutic collaborations:
There is also need for a way to regulate FSH secretion to control estrogen production in endometriosis. Currently, all estrogen production is inhibited and then low levels of estrogen are given in an add-back therapy, which is difficult to dose. However, if FSH secretion is specially regulated, and therefore estrogen production is modulated, this could provide a new way to treat endometrosis. This is something I have conceptually discussed with Dr. Agarwal, and he as spoken with Dr. Mark Lawson in our department (he studies gonadotropin production and secretion). A specific pharmacological plan has not been established and this idea is in the infantile stages.

Long term impact: 
This training has provided context to the role of the hypothalamus in clinical medicine: it’s not the most relevant factor. While my previous perception was that the hypothalamus, and the peptides produced in it, was the be-all and end-all this simply isn’t the case in the clinic. The hypothalamus and pituitary can be bypassed when treating infertility, and are suppressed in the treatment of other reproductive endocrine disorders, such as endometriosis. While the hypothalamus is obviously important for conditions like hypothalamic amenorrhea and hypogonadotropic hypogonadism, these are not common clinical presentations, and therefore are not the focus of the majority of clinical medicine and research. Our lab currently does not have access to large cohort of patients with this or related conditions, which make studying patients in the clinic difficult. However, should there become an opportunity to access patients such as these, I now have the insight and background to understand how a clinical research project could be conducted in reproductive endocrinology, and I hope to have the opportunity for that now.

Student-specific experiences:
The time commitment is clearly dependant on the track you are participating in. Reproductive medicine was half time at it’s maximum and on average at third time. Therefore it was possible for me to continue my research while participating in Med-into-Grad. Additionally, the physicians I worked with were aware of my other research obligations and were accommodating to them when possible. Med-into-Grad gives considerable context to the research one is performing in lab, and it is important to understand the how ones research fits into the bigger picture and could eventually effect patients in the clinic.

Advice for new trainees--Autumn preparatory quarter:
Take time to read through the text provided for your track before beginning your clinical work. Having this background knowledge will considerably decrease the learning curve of the first weeks in clinic and make it much easier for you to gain the full clinic experience. If you have an opportunity to go to clinic meetings before starting in the clinic, do so to learn the “physician language” so that when you are in clinic, you already have a framework to learn from.

Advice for new trainees—Winter clinical training quarter:
Find time to sit down with the physician you are working with each day to ask questions about what you don’t know. There is a lot of jargon thrown around, so using my iPhone to look up terms in clinic was extremely helpful. Physicians will also make decisions about treatments that appear to contradict that of what was decided for a previous patient; it is important to understand why these different choices were made and what it means for the outcome of that patient’s therapy. Make use of med students, since they probably know more about the clinical stuff than you, and there is less of a risk of embarrassment (since they are not the MD mentoring you). They are often very friendly as well.

Take home perspective on Med-into-Grad at UCSD: 
Med-into-Grad is a once-in-a-career opportunity. This is possibly the only time where you can get this clinical exposure short of going to medical school. As a post-doc you are really allowed to do these “extra-curricular” activities and as a professor, you are expected to have this knowledge if you want to do clinical research. So, whether or not you are going to be conducting clinical research in your future career, participating in Med-into-Grad is a very valuable experience. I would recommend Med-into-Grad to any grad student that wants to do research that is related to a disease or general physiology. Just because the condition you study has a low frequency of appearing in clinic, it doesn’t mean that Med-into-Grad is not an incredibly valuable learning experience for a young scientist.