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Obesity and Infertility

December 26, 2017



Hunter S. Clonts - Medical Student1, Zakaria Abdulla - Medical Student1, Matthew Vasey MD2


1MD Candidate, Florida International University Herbert Wertheim College of Medicine, Class of 2020
2Department of Emergency Medicine, Tampa General Hospital | TeamHealth, an affiliate of University of South Florida Morsani College of Medicine

Disclosure: Opinions reflect neither employer nor affiliated institutions, soley those of the author(s).


Polycystic Ovary Syndrome
PCOS (Polycystic ovarian syndrome) is believed to affect 6 to 10% of women between the ages of 15-49 years old and is now considered the most common cause of anovulatory infertility among reproductive aged women (7). As eager couples begin their plans to take part in the magic of conception, it is important to consider all factors that may make this plan go awry - or at least prolong the process. The prevalence of PCOS in the United States is estimated to be at 7%, and this number appears to be rising. (2) This article will explain the typical signs and symptoms of this disorder, how PCOS affects the body, the risks associated with PCOS, and treatments available to treat the condition.

Presentation
PCOS is diagnosed when 2 out of the 3 criteria are met in a female patient: 1. Signs of hyperandrogenism (increased testosterone); 2. Anovulatory cycles usually manifested in the form of oligomenorrhea; 3. "Polycystic" ovaries as seen on a transvaginal ultrasound. (7) For the majority of cases with the condition, patients present in adolescence with a lack of establishment of regular menses along with hirsutism features. (7) Hirsutism is a fancy word used to refer to abnormal hair growth patterns on a woman that typically resembles the hair growth of a man (facial hair, hair on the midline abdomen, etc.). Many times these patients are also obese, prediabetic, or have already been diagnosed with diabetes type 2. Other possible signs of PCOS are excessive depression, anxiety, acne, enlarged clitoris and irregular menstrual cycles.

How it works
While the mechanism of how this syndrome affects the body is not fully understood, there are many theories. This complex condition is thought to have both genetic and environmental influences that will continue to be studied in the clinical research trials. PCOS is a complex metabolic disease and the pathophysiology of this condition is equally as complex. However, it is clear that there are several hormone imbalance factors that lead to a state of hyperandrogenism (increased testosterone levels).

Hyperandrogenism, the cause of hirsutism and acne seen in PCOS, is partially due to low levels of progesterone. Progesterone normally acts on the brain to decrease circulating levels of luteinizing hormone (LH) in the female's body. PCOS is associated with excess LH, and insufficient amounts of follicle stimulating hormone (FSH) - the hormone that predominantly stimulates follicles in the ovary to develop during the 1st half of the female menstrual cycle before ovulation. This increase in LH and relative decrease is FSH, along with decreased levels of progesterone, are believed to be the cause of increased free testosterone levels and ovulatory dysfunction in PCOS patients. (7) Furthermore, because LH never "spikes" in the middle of these female's menstrual cycles, ovulation never occurs. Without ovulation, the follicle formed in the female ovary during the first half of the menstrual cycle never ruptures (ovulates) and thus become cysts in the ovaries. These cysts release excessive amounts of estrogen at levels high enough to positively feedback on the brain and tell it to keep releasing more LH in a vicious cycle. Thus, increased estrogen levels are also seen with this condition - more on the risks of this later.

Many women with PCOS have insulin resistance and subsequent hyperinsulinemia. Increased insulin levels further enhance ovarian androgen production and increase androgen bioavailability (how "available" the testosterone is for use in the body) by reducing levels of sex-hormone binding globulin. (7)

To conclude this mess of physiology, this hormonal imbalance between LH and FSH subsequently interferes with estrogen and progesterone levels as well as the development/functioning of ovarian follicles. The consistent hormone levels seen in a woman with PCOS mimic the early phase of the menstrual cycle, when follicular development and endometrial growth typically occur. The 'polycysts' are actually numerous follicles that have not developed properly and subsequently not ruptured/ovulated out of the ovary. In addition, the overactive endometrial growth negatively affects both uterine function and implantation (3). There is even evidence to suggest that these changes are associated with a higher risk of endometrial cancer as the increased estrogen levels in PCOS patients cause endometrial hyperproliferation (3, 5). These are some of the essential factors pertaining to our understanding of why PCOS may lead to an irregular menstrual cycle, pregnancy complications and infertility.

Risks
There is a strong association between insulin resistance and PCOS, 4 out of 5 women with insulin resistance also experience PCOS (1). Also, women with PCOS are more likely to develop dyslipidemia, gestational diabetes and type 2 diabetes mellitus (1, 8). Research currently shows that females with PCOS have lower HDL cholesterol levels, higher blood triglycerides, and higher LDL cholesterol levels than women without the syndrome - factors that significantly increase the risk of cardiovascular disease. (7) Therefore, women with PCOS should be frequently screened for dysglycemia and dyslipidemia, especially when pregnant. Gestational diabetes can lead to many complications and risks for both the mother and fetus. Mothers should maintain a close eye on their blood pressure as well any increased swelling in their hands and/or feet during pregnancy, as these are signs that could indicate preeclampsia in a woman at or beyond 20 weeks gestation. In addition to these risks, the risk of endometrial cancer is estimated to be 2.7 times as high among women with PCOS as among women without the syndrome. (3,5,7) The risk factors for endometrial cancer in these women are anovulation, obesity, and insulin resistance. (7)

Treatment
Treatment for PCOS is largely determined by if the woman in question wishes to still be able to become pregnant or not. Typical PCOS treatments aim to reduce hirsutism caused by increased testosterone, prevent irregular menstrual cycles and lower the risk of endometrial cancer, and lastly to regain fertility (if the patient wishes to become pregnant). In addition to these medical treatments, weight loss is also indicated as a treatment for PCOS as it has been shown to improve insulin resistance, reduce androgen levels, and improve menstrual function and possibly fertility. (7)

The gold standard treatment for women with PCOS who have no plans to get pregnant is currently an oral combined hormonal (estrogen-progestin) contraceptive pill. (7) This birth control pill helps restore regular menstrual cycle bleeding and lower androgen levels. Furthermore, an oral drug named spironolactone may be added to the regiment as an androgen receptor blocker to further prevent hirsutism from recurring. Metformin (a diabetic drug) is also taken by women with PCOS to reduce hyperinsulinemia associated with the syndrome; this drug is also believed to improve ovulatory dysfunction. (7) For women who wish to get pregnant while battling PCOS, clomiphene is considered the first line agent to induce ovulation and increase chances of conception. (7)

REFERENCES:
1. A. E. Joham, S. Ranasinha, S. Zoungas, L. Moran, H. J. Teede; Gestational Diabetes and Type 2 Diabetes in Reproductive-Aged Women With Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism. Volume 99, Issue 3, 1 March 2014, Pages E447-E452, https://doi.org/10.1210/jc.2013-2007
2. Abdel-Rahman MY, Jackson LW, Rodewald KJ, Abdellah MA, Ismail SA, Hurd WW. Polycystic ovary syndrome and diabetes screening: a survey of gynecologists and reproductive endocrinologists. Eur J Obstet Gynecol Reprod Biol. 2012 Jun;162(2):178-81. doi: 10.1016/j.ejogrb.2012.03.007. Epub 2012 Mar 30. PubMed PMID: 22464207.
3. Ferreira SR, Motta AB. Uterine function: from normal to Polycystic Ovarian Syndrome alterations. Curr Med Chem. 2017 Dec 5. doi: 10.2174/0929867325666171205144119. [Epub ahead of print] PubMed PMID: 29210631.
4. Grigoryan OR, Zhemaite NS, Volevodz NN, Andreeva EN, Melnichenko GA, Dedov II. [Long-term consequences of polycystic ovary syndrome]. Ter Arkh. 2017;89(10):75-79. doi: 10.17116/terarkh2017891075-79. Russian. PubMed PMID: 29171475.
5. Harris HR, Babic A, Webb PM, Nagle CM, Jordan SJ, Risch HA, Rossing MA, Doherty JA, Goodman MT, Modugno F, Ness RB, Moysich KB, Kjaer SK, H√łgdall E, Jensen A, Schildkraut JM, Berchuck A, Cramer DW, Bandera EV, Wentzensen N, Kotsopoulos J, Narod SA, Phelan CM, McLaughlin JR, Anton-Culver H, Ziogas A, Pearce CL, Wu AH, Terry KL. Polycystic ovary syndrome, oligomenorrhea, and risk of ovarian cancer histotypes: Evidence from the Ovarian Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev. 2017 Nov 15. pii: cebp.0655.2017. doi: 10.1158/1055-9965.EPI-17-0655. [Epub ahead of print] PubMed PMID: 29141849.
6. Kim JY, Tfayli H, Michaliszyn SF, Arslanian S. Impaired Lipolysis, Diminished Fat Oxidation and Metabolic Inflexibility in Obese Girls with Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017 Dec 6. doi: 10.1210/jc.2017-01958. [Epub ahead of print] PubMed PMID: 29220530.
7. McCartney ChR, Marshall JC. Polycystic Ovary Syndrome. N Engl J Med. 2016 Oct 6;375(14):1398-1399. doi: 10.1056/NEJMc1610000. PubMed PMID: 27705264.
8. Wang ET, Calderon-Margalit R, Cedars MI, et al. Polycystic Ovary Syndrome and Risk for Long-Term Diabetes and Dyslipidemia. Obstetrics and gynecology. 2011;117(1):6-13. doi:10.1097/AOG.0b013e31820209bb.
9. A. E. Joham, S. Ranasinha, S. Zoungas, L. Moran, H. J. Teede; Gestational Diabetes and Type 2 Diabetes in Reproductive-Aged Women With Polycystic Ovary Syndrome. The Journal of Clinical Endocrinology & Metabolism. Volume 99, Issue 3, 1 March 2014, Pages E447-E452, https://doi.org/10.1210/jc.2013-2007



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