Insulin Resistance and Fertility: Part 2

Part 2: How does Insulin Resistance (IR) affect Fertility?

Originally published by Dr. Fiona McCulloch in Naturopathic Currents in September 2013, you can read the original article here.

This article has been broken down into a four part series, links to the other parts of this series are listed below:

Polycystic Ovarian Syndrome

The most well known insulin resistant condition that affects fertility is polycystic ovarian syndrome (PCOS). PCOS is a condition that has many variations. It includes characteristics such as irregular ovulation or menstrual cycles, androgenic/male hormone related signs such as hirsutism (excessive hair growth), acne or male pattern hair loss, abdominal obesity. Some women with PCOS have multiple small follicles (cysts) from eggs that never developed fully in the ovary. There might also be blood markers for insulin resistance, hormonal abnormalities like increased LH to FSH ratio, high estrogen, and/or high androgens such as free testosterone. There are several variants of PCOS that contain different combinations of the aforementioned signs and symptoms.

In PCOS, high insulin levels cause the follicles in the ovary to produce male hormones. These male hormones (androgens) slow down the development of the follicles and can even stop ovulation altogether.

High amounts of insulin also cause fat cells to convert testosterone into estrogen, a process known as aromatization. High estrogen levels increase the pituitary gland’s secretion of luteinizing hormone (LH), which results in even more testosterone release from the ovary. Truly a “vicious cycle”. High estrogen also suppresses follicle-stimulating hormone (FSH), causing the eggs to develop poorly.

Insulin resistance causes even more problems with hormones. It lowers sex hormone binding globulin (SHBG),(1) which normally binds up hormones and keeps them from activating tissue receptors. When SHBG is low, there are more androgens freely floating in the bloodstream, available to act on tissues and therefore produce androgenic effects.

For patients with PCOS, insulin resistance is always a part of the condition, regardless of whether a woman is slim or overweight.(2) Patients with PCOS are particularly sensitive to the effects of extra weight however, when compared to control females who do not have PCOS. As more fatty tissue further aggravates insulin resistance, patients with PCOS need to aim for a lower BMI to promote optimal reproductive health.

Moreover, insulin resistance in PCOS is associated with inflammation. Certain inflammatory factors have been found to be high in women with PCOS. These same markers (C – reactive protein and homocysteine) are also potential factors in miscarriage and implantation failure .(3) Women with PCOS are at an increased risk for miscarriage when compared to the general population.

  • Obesity

Insulin resistance increases sharply at a BMI level of 27 and above.(4) Obesity has well documented effects on reproduction, much of which is attributed to insulin resistance. Patients who are obese have higher miscarriage rates, and lower rates of success in assisted reproductive technologies such as IVF.(5) Obese women with PCOS have even more problems with fertility when compared to lean PCOS women. This is because high BMI greatly aggravates the underlying insulin resistant state that is already present in PCOS.

A high BMI is also associated with increased blood and follicular leptin concentrations.(6) Leptin is a hormone that inhibits appetite and regulates calorie expenditure. Leptin typically is higher in overweight people, and lower in those who are lean. It inhibits appetite by acting on the hypothalamus of the brain. In cases of obesity however, it is thought that the cells become resistant to leptin. High levels of leptin without the corresponding reduction in appetite contribute to even more weight gain. Leptin also acts on the granulosa cells in the ovary, inhibiting the production of hormones by the ovary, and affecting the function and quality of the follicles.(7)

High BMI is also associated with lower serum adiponectin levels.(8) Adiponectin is a fat specific protein that prevents arterial plaques and is anti-inflammatory. Adiponectin is lower in patients with obesity, type 2 diabetes and cardiovascular disease.

Low adiponectin(8) levels in obese women also decrease Sex Hormone Binding Globulin (SHBG), and thereby increase free male hormones in a similar fashion to PCOS. High free androgens disrupt the normal ovarian cycle, and impair egg quality.

Obesity also produces chronic low-grade inflammation. Inflammation has been associated with different fertility conditions such as implantation failure and recurrent miscarriage. A study on mouse models of obesity found elevated inflammatory markers interleukin-6, TNF-alpha and CRP, all of which have been associated with infertility.(9)

  • Miscarriage

Insulin resistance has also been implicated in recurrent miscarriage. A study on 74 women with recurrent pregnancy loss (rpl) found that 27% had insulin resistance, compared to 9.5% of matched controls.(10) Another large study suggested that insulin resistance was an independent risk factor for recurrent miscarriages, even when controlled for PCOS.(11)

Article References:

  1. Jayagopal V, Kilpatrick ES, Jennings PE, Hepburn DA, Atkin SLThe biological variation of testosterone and sex hormone-binding globulin (SHBG) in polycystic ovarian syndrome: implications for SHBG as a surrogate marker of insulin resistanceJ ClinEndocrinolMetab2003 Apr;88(4):1528-33.
  2. Stepto NK, Cassar S, Joham AE, Hutchison SK, Harrison CL, Goldstein RF, Teede HJWomen with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clampHum Reprod2013 Mar;28(3):777-84.Epub 2013 Jan 12
  3. Tarkun I, Arslan BC, Cantürk Z, Türemen E, Sahin T, Duman CEndothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammationJ ClinEndocrinolMetab2004 Nov;89(11):5592-6.
  4. Campbell PJ, Gerich JEImpact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesityJ ClinEndocrinolMetab1990 Apr;70(4):1114-8.
  5. Moragianni VA, Jones SM, Ryley DAThe effect of body mass index on the outcomes of first assisted reproductive technology cyclesFertilSteril2012 Jul;98(1):102-8.
  6. Metwally M, Li TC, Ledger WLThe impact of obesity on female reproductive functionObesity Rev2007;:515-23.
  7. Moschos S, Chan JL, Mantzoros CSLeptin and reproduction: A reviewFertilSteril2002;:433-44.
  8. Gil-Campos M, Canete RR, Gil AAdiponectin, the missing link in insulin resistance and obesityClinNutr2004;:963-74.
  9. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen HChronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistanceJ Clin Invest2003 Dec;112(12):1821-30.
  10. LaTasha B Craig, Raymond W Ke, William H KuttehIncreased prevalence of insulin resistance in women with a history of recurrent pregnancy lossFertility and SterilitySeptember 2002;78(3):487-490.
  11. Lashen H, Fear K, Sturdee DWObesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control studyHum Reprod2004 Jul;19(7):1644-6.