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Polycystic Ovary Syndrome ' Patient Vignette

On physical examination, she was 5 feet 5 inches tall, weighed 125 pounds, and had normal blood pressure. Her complexion was clear. Any emerging hair from her chin was readily plucked before being noticeable. On vaginal ultrasound, her ovaries were plump. Each had a string of more than 30 small follicles lined up along the periphery. Her uterine lining was thin and only measured 4mm. Her laboratory tests were as follows: cycle day 3 follicle stimulating hormone (FSH) 6.5mIU/mL, luteinizing hormone (LH) 20.4 mIU/mL, total testosterone 93 ng/dL, 17-hydroxy progesterone (17OHP) 94 ng/dL, anti-mullerian hormone (AMH) 12.7 ng/mL, fasting glucose 86 mg/dL, and hemoglobin A1C (HbA1C) 6.0 percent.

Like most of us nowadays, she had spent hours browsing the Internet prior to her consultation, and had come to the conclusion that she has polycystic ovary syndrome (PCOS). After reviewing her history and testing, I agreed with her self-diagnosis.

PCOS is characterized by high levels of androgens (hormones associated with male sexual characteristics) either by clinical manifestations or by laboratory testing; anovulation or oligo-ovulation (infrequent or absent ovulation); ovaries showing a “string of pearls”, which are multiple follicles aligned under the capsule of the ovary; and the exclusion of other reasons for these signs and symptoms such as adult onset congenital adrenal hyperplasia (1,2,3).

PCOS is a fairly common condition, afflicting 7 to 10 percent of reproductive-aged women. Some PCOS patients are lean, but the majority of women with PCOS (80 percent) are overweight or obese. Blood tests might show elevated LH, often in two-fold excess to FSH.

Women with PCOS often seek medical care because of irregular menstrual cycles and infertility. Accompanying symptoms may be acne, hair on lips and chin, and male pattern hair loss. Those with chronically infrequent menstruation may develop precancerous overgrowth of their uterine lining (endometrial hyperplasia) requiring hormonal or surgical treatment. When women with PCOS become pregnant, they have increased risks of first trimester miscarriage, pregnancy-induced diabetes, and high blood pressure (4,5). PCOS patients undergoing assisted reproductive technologies are at higher risk of complications of treatment such as ovarian hyperstimulation syndrome (OHSS) and multiple gestations.

Aside from their reproductive risks, women with PCOS are more likely to have metabolic abnormalities, with increased risk of heart disease later on in life (4,5). Lean PCOS women have a 3 to 10 percent incidence of undiagnosed diabetes, with higher risk in patients with obesity (4). Up to 40 percent of PCOS patients will have a prediabetic condition called impaired glucose tolerance (IGT) caused by their body’s resistance against insulin which is the hormone that helps our cells break down sugar into energy. Signs of insulin resistance include darker, thick, velvety skin in body folds and creases (acanthosis nigracans) and accumulation of fat at the waist area (central obesity). Impaired glucose tolerance, or insulin resistance, is an important condition to recognize because 54 percent will convert to type II diabetes in 6 years (5). Measuring fasting blood sugar levels does not capture everyone with IGT in PCOS patients because only 7.5 percent will test positive (100-125 mg/dL) (5). Two additional tests are the glucose tolerance test where the blood sugar levels are measured 2 hours after ingesting a sugary drink containing 75g of glucose (IGT: 140-199 mg/dL); and measuring blood levels of hemoglobin A1C (IGT: 5.7-6.4 percent).

In addition to sugar metabolism and obesity, 70 percent of PCOS women will have high cholesterol or triglyceride (4). The constellation of metabolic abnormalities including impaired glucose tolerance, high blood pressure, high cholesterol, and central distribution of body fat is recognized as a separate medical entity called the metabolic syndrome. Women with metabolic syndrome have an elevated risk of cardiovascular problems (5). Because of the metabolic and cardiovascular sequelae, any patient who is suspected of PCOS should undergo a comprehensive workup including an assessment of her glucose tolerance, blood pressure, fasting lipids, and measurements of central obesity.

My patient Casey presented with infrequent menstrual cycles but not androgen excess or metabolic abnormalities. On laboratory testing, she had hormonal profiles characteristic of classic PCOS including high LH to FSH ratio of greater than 2 (although no longer a diagnostic criteria), elevated testosterone levels, and polycystic ovaries. Despite being thin, normotensive, and having normal levels of fasting glucose, she did have elevated hemoglobin A1C levels, which measured average blood sugar levels over the past 2 to 3 months. Treatments for Casey should be two pronged: improving her chances of healthy pregnancy and reducing her future risks of diabetes and heart disease.

Treatment of infertility in PCOS patients starts with ovulation induction. The ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group recommended clomiphene citrate as first line therapy. Clomiphene is a selective estrogen receptor modulator (SERM) that tricks the hypothalamus, our reproductive control center in the brain, to stimulate more production of our own FSH from the pituitary and thereby indirectly induce ovulation in our ovaries (6). Overall, 80 percent of PCOS patients will ovulate on clomiphene.

Because of the associated metabolic abnormalities, an anti-diabetic agent called metformin has also been used in PCOS patients to induce ovulation. In early studies, metformin showed promising results. However, in later and larger randomized controlled trials, clomiphene citrate alone had a superior live birth rate compared to metformin alone, and was equally as effective as the combination of clomiphene and metformin (7,8). Therefore, the Consensus Workshop Group recommended against using metformin alone, or in combination with clomiphene unless the patient demonstrates insulin resistance or impaired glucose tolerance. For the 20 percent of patients who are unresponsive to clomiphene, an aromatase inhibitor called letrozole, classically used as an anti-breast cancer medication, has been found to be very effective in inducing ovulation. Ultimately, some PCOS patients will prove to be clomiphene and letrozole “resistant”, meaning that they fail to ovulate on either medication. They will require daily injectable FSH or sometimes even in-vitro fertilization (IVF) to successfully conceive.

I started Casey on metformin because her elevated hemoglobin A1C levels suggested abnormal glucose metabolism which increased her future cardiovascular risk. After 3 months of treatment as well as modification of her diet to decrease simple sugar and carbohydrates, her A1C levels were lowered to 5.3 percent which were in the normal range. During that time, we tried ovulation induction unsuccessfully with clomiphene and letrozole. Her follicles were stubbornly resistant and refused to ovulate. We attempted daily injectable FSH to directly stimulate her follicles to grow. Unfortunately, she developed hyperstimulation on even the lowest dose of FSH, which was a consequence of her youth and high egg count. Hyperstimulation of PCOS patients on injectable FSH is not uncommon and can be very dangerous, leading to twins and triplets or even more. Therefore, Casey’s cycle was canceled.

We realized that IVF would be the only effective and the safest method for Casey to achieve a healthy pregnancy. IVF can reduce the risk of multiple gestations by controlling the number of embryos to transfer back into the uterus. Casey underwent her first cycle of IVF and had 17 mature eggs harvested. These 17 eggs gave rise to 9 beautiful embryos. One embryo was transferred, an elective Single Embryo Transfer (eSET), and the rest were frozen. She conceived a singleton pregnancy.

This May, we heard the wonderful news that she gave birth to a healthy 9-pound baby boy named Kyle. She did not experience any complications during pregnancy, not even gestational diabetes. Despite all her trials and tribulations, I suspect that it won’t be too long before she comes knocking on PFC’s door for one of Kyle’s frozen siblings.

References:

1. Dunaif A, Givens JR, Haseltine FP, Merriam GR, editors. Polycystic ovary syndrome. Boston (MA): Blackwell Scientific Publications; 1992.
2. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Fertil Steril 2004;81:19–25.
3. Azziz R, Carmina E, et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. Androgen Excess Society. J Clin Endocrinol Metab 2006;91:4237–45.
4. Polycystic Ovary Syndrome. ACOG Practice Bulletin, Number 108, October 2009, Reaffirmed 2011.
5. Fauser BC, Tarlatzis BC, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012 Jan;97(1):28-38.e25.
6. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril. 2008;89(3):505
7. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER, Cooperative Multicenter Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356(6):551
8. Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev. 2012;5

- Liyun Li, M.D.

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