CASE 45
A 22-year-old woman enters your clinic with the chief complaint of irregular menstrual periods. She indicates that she was 14 when her periods first started and that they had never really been very regular. On physical examination she is 5′4″ and weighs 195 lb. She has mild acne on her face and shoulders and a more-than-normal amount of facial hair. There is a darkening of the skin at the base of her neck and across her shoulders. Blood tests reveal an elevated LH and a normal FSH level (LH/FSH 3.2). You suspect she may have polycystic ovary syndrome (PCOS) and start her on metformin.
What is the effect of insulin on the ovaries?
What is the mechanism of action of metformin?
ANSWERS TO CASE 45:
Agents for the Treatment of PCOS
Summary: A 22-year-old woman with obesity, hirsutism, and irregular menstrual cycles, consistent with the diagnosis of PCOS.
Effect of insulin on the ovaries: Insulin stimulates steroidogenesis, especially androgen production within the ovary.
Mechanism of action of metformin: Metformin activates AMP kinase; this central regulator of metabolism acts to increase glucose uptake and metabolism in skeletal muscle and decrease glucose production in the liver.
CLINICAL CORRELATIONS
PCOS is a very common cause of irregular menstrual periods and infertility. It is frequently associated with obesity and the concomitant insulin resistance and hyperinsulinemia. The excessive insulin increases production of ovarian androgens such as androstenedione and dehydroepiandrosterone, which can act peripherally and increase both sebum production and hair growth. Acanthosis nigricans (darkened shoulders) is a manifestation of hyperinsulinemia. Metformin is an oral antidiabetic agent that causes metabolic changes that decrease serum glucose and insulin levels.
APPROACH TO:
PCOS
OBJECTIVES
1. Know the agents for the treatment of PCOS.
2. Know the mechanism of action, uses, and adverse effects of the agents.
DEFINITIONS
PCOS: Polycystic ovary syndrome (also known as Stein-Leventhal syndrome or polycystic ovary disease [PCOD]) is one of the leading causes of infertility in women.
Acanthosis nigricans: A velvety darkening of the skin commonly seen at the nape of the neck, elbows, axilla, and knuckles usually caused by hyperinsulinemia.
DISCUSSION
PCOS is characterized by a lack of regular ovulation and excessive amounts or effects of androgenic (masculinizing) hormones. The ovaries accumulate benign cysts produced by abnormal follicular development and lack of ovulation due to endocrine dysfunction. Patients with PCOS tend to have high body mass index (BMI), glucose intolerance, and insulin resistance. The elevated insulin level due to the insulin resistance is a potent stimulator of steroidogenesis, especially of androgens, in the ovary. The androgens cause acne and hirsutism, both frequently associated with PCOS. Hyperinsulinemia increases GnRH pulse frequency, LH over FSH dominance, decreased follicular maturation, and decreased sex hormone–binding globulin; all these steps contribute to the development of PCOS.
Metformin is a biguanide oral antihyperglycemic agent. It appears to act by activating AMP kinase, an important metabolic integrator with effects on adipose tissue, skeletal muscle, cardiac muscle, liver, and hypothalamus. Activation of AMP kinase reduces glycogen production, reduces fatty acid oxidation, and facilitates glucose uptake.
In PCOS patients, metformin reduces insulin resistance and lowers insulin levels, which lowers serum androgen concentrations, restores normal menstrual cycles and ovulation, and may help to resolve PCOS-associated infertility. Metformin, when administered to lean, overweight, and moderately obese women with PCOS, has been found to significantly reduce serum luteinizing hormone (LH) and increase FSH and sex hormone–binding globulin (SHBG). Serum testosterone concentrations were also found to decrease by approximately 50 percent.
GI adverse effects are seen in approximately 30 percent of patients taking metformin. GI effects include anorexia, nausea/vomiting, abdominal discomfort, dyspepsia, flatulence, diarrhea, and dysgeusia (metallic taste). These side effects tend to decline with continued use and can be minimized by initiating therapy with low doses of metformin. Asymptomatic vitamin B12 deficiency was reported with metformin monotherapy in 9 percent of patients during clinical trials. The risk of hypoglycemia is much less common with metformin than with the sulfonylureas.
Other agents that are used to treat PCOS include oral contraceptives, which reduce LH and ovarian androgen production and finasteride, a potent 5α-reductase inhibitor (see Case 40). In PCOS patients desiring to become pregnant, clomiphene induces ovulation in about 45 percent. In patients unsuccessfully treated with clomiphene alone, addition of metformin may increase the ovulation and conception rates.
COMPREHENSION QUESTIONS
45.1 Which of the following would be the best agent to use in a patient with PCOS?
A. Pioglitazone
B. Metformin
C. Regular insulin
D. Repaglinide
45.2 Which of the following is the most common adverse effect of metformin?
A. Hypoglycemia
B. Hyperinsulinemia
C. GI effects
D. Pruritis
45.3 Which of the following is the mechanism of action of metformin?
A. Increase insulin secretion by the pancreas
B. Increase hepatic sensitivity to insulin
C. Reduction in DHT production
D. Increased muscle uptake of glucose
ANSWERS
45.1 B. Pioglitozone, as an insulin sensitizer, might be efficacious in the treatment of PCOS but metformin has fewer and less severe side effects. Repaglinide stimulates insulin secretion, which would be detrimental in PCOS.
45.2 C. Metformin infrequently causes hypoglycemia and hypersensitivity reactions, for instance in the skin, are rare.
45.3 D. Metformin does not increase insulin production; it appears to act by decreasing plasma glucose by affecting metabolism rather than altering the sensitivity of tissues to insulin.
PHARMACOLOGY PEARLS
Metformin reduces insulin levels and can improve insulin sensitivity without weight gain.
Metformin rarely causes hypoglycemia.
REFERENCES
Bhathena RK. Therapeutic options in the polycyctic ovary syndrome. J Obstet Gynaecol. 2007;27:123–9.
Shannon M, Wang Y. Polycystic ovary syndrome: a common but often unrecognized condition. J Midwifery Womens Health. 2012;57:221–30.
Palomba S, Falbo A, Zullo F. Management strategies for ovulation induction in women with polycystic ovary syndrome and known clomifene citrate resistance. Curr Opin Obstet Gynecol. 2009;21:465–73.