Work Code: C620R9013
Routine Use of Insulin Sensitizing Agents
J.E. Buster
Professor of Obstetrics and Gynecology, Director, Division of Reproductive Endocrinology &
Infertility, Baylor College of Medicine, Houston, Texas, U.S.A.
Insulin resistance is now recognized as an integral mechanism in the pathogenesis of the
polycystic ovarian syndrome (PCOS).(1) (2) Compensatory hyperinsulinemia and dyslipidemia
occur as a consequence of insulin resistance. It is believed that the hyperinsulinemia of PCOS
promotes or facilitates excess androgen production which in turn is related to the chronic
anovulation state that characterizes PCOS. Insulin sensitizing drugs can be used alone to enhance
spontaneous ovulation or to augment induction of ovulation with other drugs in PCOS. The
traditional approach to ovulation induction with PCOS had been to use clomiphene citrate as first
line followed by gonadotropin administration when clomiphene citrate is unsuccessful. The
introduction of insulin sensitizing agents is dramatically altering this tradition.
Insulin Resistence, Hyperinsulinemia, and PCOS
Both lean and obese women afflicted with PCOS are insulin resistant. In the case of lean women,
it is believed that these patients have a form of insulin resistance that is intrinsic to the
syndrome.(3) (4) In obese women, the fat mass serves an added burden of insulin resistance.
Most clinicians experienced with PCOS no longer attempt to document insulin resistance. It is
presumed that all have the feature.(5) Weight loss through diet and exercise enhances ovulation
for PCOS women. Accordingly, it is always prudent to first recommend weight loss and exercise
to reduce insulin resistance. In today's clinical environment, however this is difficult even though
patients are strongly driven to conceive. Weight loss is rarely successful. Availability of insulin
sensitizing drugs discourages weight loss because the patients know this option exists.
Insulin Sensitizing Drugs
Insulin sensitizing drugs, when administered to insulin resistant patients, increase target tissue
response to insulin. They reduce the need for compensatory hyperinsulinemia. Three drugs have
been studied: (1)metformin; (2)troglitazone, and (3)d-chiro-inositol. Of these three drugs,
metformin is the most extensively studied.(6) (11)
Metformin
Metformin is a second generation biguamide. Metformin decreases peripheral insulin resistance
and lowers serum glucose by actively augumenting glucose transporters which allows passage of
glucose into hepatic and muscle cells. It does not stimulate insulin release and does not cause
hypoglycemia.
Metformin is normally administered in a dose of 500/mg tid (1500 mg/daily).(8) When
administered alone, in many patients it induces timely menstrual cyclicity, enhances spontaneous
ovulation, and therefore promotes fertility. Reports today are all case series. Thus in a recent
report, in 48 patients diagnosed with PCOS, metformin successfully promotes timely ovulation
in 19/48.(12) An additional 15/48 women required clomiphene citrate to ovulate. While 20/48
conceived, unfortunately 5/20 miscarried (35% miscarriages). The protocol utilized metformin
given in 500 mg bid for six weeks and then increased to 500 mg tid for six weeks. (12)
Clomiphene citrate 50 mg was added when ovulation was not restored on the metformin alone.
Very heavy women do not respond well to metformin.(13) (14) (15)
Troglitazone
Troglitazone belongs to a group of anti diabetic agents, thiazolidinediones. Drugs that belong to
this group decrease peripheral insulin resistance by binding to the peroxisone proliferation
activator gamma receptor. Short term treatment with troglitazone results in continuation of
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Work Code: C620R9013
insulin resistance, reduction in insulin secretion, and decrease in androgen levels.(16)
Unfortunately, this drug was associated with cases of hepatic nectosis and was withdrawn by the
FDA.
D-Chiro –inositol
This drug is not yet commercially available. In a randomized double blind pharmaceutical trial it
was successful in inducing ovulation with PCOS patients.(17)
Insulin Sensitizing Drugs and Clomophine Citrate
Insulin sensitizing are drugs which augment the ovulatory response to clomiphene citrate.(8)
Metformin is now known highly effective in patients who have failed with clomiphene citrate.
When started on metformin these patients ovulate successfully, even at a lower dose of the
clomiphene. In one randomized trial, metformin was given to patients who had documented
failures to clomiphene at doses as high as 150 mg.(18) Significant improvements in ovulatory
frequency and pregnancy was observed in the women treated with clomiphene citrate and
metformin.(18)
Insulin Sensitizing Drugs and Gonadotropins
The effects of metformin given in combination with gonadotropin have been documented only in
one case series. Women afflicted with PCOS frequently have hyperstimulation in response to
exogenous FSH. In a small cases series, the number of follicles seen at ≥15 mm on the day of
HCG administer is significantly lower in women pre treated with metformin. Furthermore,
cancellation rates were decreased in pre treated women. This experience suggests that metformin
pre treatment will reduce hyperstimulation rates.(19)
Metformin and IVF
There is only one small case series of metformin pre treatment with IVF. In this experience,
metformin increased the number of mature oocytes, fertilization rates, and the number of
embryos produced.(20)
Metformin and Early Pregnancy Loss
Women afflicted with PCOS have abnormally high miscarriage rates, as high as 30 to 50% of
pregnancies. Conversely, 36 to 82% of women with recurrent pregnancy loss have been reported
to have PCOS.(21 – 27)
Accordingly, the intriguing notion exists that the dysfunctional ovulation of PCOS may be a
factor in early recurrent pregnancy loss. Accordingly administration of insulin sensitizing drugs
might be helpful in reducing losses. Thus in a recent pilot study, there was a dramatic reduction
in pregnancy loss to women with PCOS treated with metformin. (28) (29) This is problematic in
that metformin is a category B drug which means teratogenic affects have been yet demonstrated
in animals. It is reassuring however, to note that no excess of teratogenic effects have been
reported in human subjects.
Side Effects
Lactic acidosis with metformin is rare.
The principle side effects to metformin are gastrointestinal, particularly abdominal cramping and
diarrhea. These can be avoided by using the drug in gradual increased doses over several weeks.
For patients undergoing hysterosalpingography (HSG), it is better to discontinue this drug
because of concern for lactic acidosis, HSG studies should be preformed prior to implementing
this therapy.
As a category B drug its safety profile pregnancy appears to be acceptable.
Treatment Protocols
There is no standard metformin regimen.
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Work Code: C620R9013
In one recent study, metformin was administered 500 mg bid for six weeks followed by
increasing doses of 500 mg tid for six weeks. If ovulation induction was not successful at 500 mg
tid clomiphene citrate was added. (12)
A more rapid approach is to begin metformin with 500 mg bid and add clomiphene citrate at
50 mg per day for the first five days of the cycle. A head to head trial is currently underway by
the NIH sponsored Reproductive Medicine Network.(8)
In cases where there has been failure with clomiphene citrate at 150 mg, the clomiphene is
discontinued, metformin is begun at 500 mg bid and clomiphene citrate is then readministered at
50 mg per day. (18)
Summary
The addition of insulin sensitizing drugs is arguably the most significant addition to the
treatment of PCOS in the last decade. The enhancement of insulin effect frequently restores
ovulation in of itself. It also augments the effect of other ovulation induction regimens. It also
may be effective in some cases of recurrent miscarriages.
The use of insulin sensitizing drugs for treatment of reproductive disorders has not been
approved by FDA. It is nonetheless in widespread use by reproductive endocrinologists. Methods
to optimize ethicasey will be the focus of continued research.
References
1. Chang, RJ, Nakamura, RM, Judd, HL, Kaplan SA. Insulin resistance in nonobese
patients with polycystic ovarian disease. J Clin Endocrinol Metab 1983; 57: 3569.
2. Dunaif A, Segal Kr, Futterweit W, Dobrijansky A. Evidence for distinctive and
intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes 1992,
41:1257-66.
3. Ciaraldi TP el Roceiy A, Madar Z, Reichart, D, Olefsky JM, Yenn, SSC. Cellular
mechanisms of insulin resistance in polycystic ovarian syndrome. J Clin
Endocrinol Metab 1992;75:577-83.
4. Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine
phosphorylation in cultured fibroblasts and in skeletal muscle. A potential
mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest
1995;96:801-10.
5. Nestler JE, Stovall D, Akhter N, Iumo M, Jakubowicz D. Strategies for the use of
insulin-sensitizing drugs to treat infertility in women with polycystic ovary
syndrome. Fertility Sterility 2002;77:209.
6. Velazquez Em, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in
polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance,
hyperandrogenemia, and systolic blood pressure, while facilitating normal menses
and pregnancy. Metabolism 1994; 43:647-54.
7. Velazques E, Acosta A, Mendoza, SG. Menstrual cyclicity after metformin
therapy in polycystic ovary syndrome. Obstet Gynecol 1997, 90:392-95.
8. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on
spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.
N Engl J Med 1998;1876-80.
9. Glueck Cj, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced
resumption of normal menses in 39 of 43 (91%) previously amenorrheic women
with the polycystic ovary syndrome. Metabolism 1999;48:511-9.
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Work Code: C620R9013
10. Moghetti P, Castello R, Negri C, Tosi F, Perone F, Caputo M, et al. Metformin
effects on clinical features, endocrine and metabolic profiles, and insulin
sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebocontrolled 6-month trial, followed by open, long-term clinical evaluation. J clin
Endocrinol Metab 2000;85:139-46.
11. Pasquali R, Gambineri A, Biscotti C, Vicennati V, Gagliardi, L, Colitta D, et al.
Effect of long-term treatment with metformin added to hypocaloric diet on body
composition, fat distribution, and androgen and insulin levels in abdominally
obese women with and without the polycystic ovary syndrome. J Clin
Endoocrinol Metab 2000;85:2767-74.
12. Heard MJ, Pierce A, Carson, SA, and Buster, JE. Pregnancies following use of
metformin for ovulation induction in patients with polycystic ovary syndrome.
Fertility Sterility 2002, 77: 669.
13. Campbell PJ. Gerich JE. Impact of obesity on insulin action in volunteers will
with normal glucose tolerance: demonstration of a threshold for the adverse effect
of obesity. J Clin Endocrinol Metab 1990;70:1114-8.
14. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond
to insulin reduction with decrease in ovarian P450c17a activity and serum
androgens. J Clin Endocrinol Metab 1997;82:4075-9.
15. Ehrmann Da, Cavaghan MK, Imperial J, Sturis J, Rosenfield RL, Polonsky, KS.
Effects of metformin on insulin secretion, insulin action, and ovarian
steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol
Metab 1997;82:524-30.
16. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, et al.
Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome:
a multicenter, double-blind, placebo-controlled trial. J Clin Endocrinol Metab
2001:86:1626-32.
17. Nestler JE, Jakubowiez DJ, Reamer P, Gunn R, Allan G. Ovulatory and metabolic
effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med
1999;340:1314-20.
18. Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE.
Metformin increases the ovulatory rate and pregnancy rate from clomiphene
citrate in patients with polycystic ovary syndrome who are resistant to clomiphene
citrate alone. Fertility Sterility 2001;75:310-5.
19. De Leo V, la Marca A, Ditto A, Morgante G, Cianci A. Effects of metformin on
gonadotropin-induced ovulation in women with polycystic ovary syndrome. Fertil
Sterility 1999;72:282-85.
20. Stadmauer LA, Riehl RM, toma SK, Huang S, Barker s, and Talbert LM.
Metformin treatment of patients with polycystic ovarian syndrome undergoing
IVF increase the number of mature oocytes, the fertilization rate and the number
of embryos with changes in the levels of insulin-like growth factors. Abstracts of
the American Society for Reproductive Medicine 1999;72:812.
21. Balen AH, Tan SL, MacDougall J, Jacobs, HS. Miscarriage rates following invitro fertilization are incrased in women with polycystic ovaries and reduced by
pituitary desensitization with buserelin. Human Reprod 1993;8:959-64.
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Work Code: C620R9013
22. Homburg R, Amar NA, Eshel A, Adams J, Jacobs HS. Influence of serum
luteinizing hormone concentrations on ovulation, conception, and early pregnancy
loss in polycystic ovary syndrome. BMJ 1988;297:1024-6.
23. Regan L, Owen EJ, Jacobs, HS. Hypersecretion of luteinizing hormone,
infertility, and miscarriage. Lancet I1990;336:1141-4.
24. Sagle M, ishop K, Ridley N, Alexander FM, Michel M, Bonney RC, et al.
Recurrent early miscarriage ena polycystic ovaries. BMJ 1998;807:1027-8.
25. Watson H, Kiddy DS, Hamilton-Fairley D, Scanlon MJ, Barnard C, Collins WP,
et al. Hypersecretion of luteinizing hormone and ovarian steroids in women with
recurrent early miscarriage. Hum Reprod 1993;8:829-33.
26. Middell HS, Sowden K, Farqhar CM. Recurrent miscarriage: screening for
polycystic ovaries and subsequent pregnancy outcome. Aust N Z J Obstet
Gynaecol, 1997;37:402-6.
27. Fedorosak P, Storeng R, Dale PO, Tambo T, Abybolin T. Obesity is a risk
factor for erly pregnancy loss after IVF or ICSI. Acta Obstet Obstet Gynecol
Scand 2000;79:43-8.
28. Clueck CJ, Phillips H, Cameron D, Sieve-Smith L, Wang P. Continuing
metformin throughout pregnancy in women with polycystic ovary syndrome
appears to safely reduce first-trimester spontaneous abortion: a pilot study.
Fertility Sterility 2001;75:46-52.
29. Jakubowicz DJ, Luorno MJ, Jakubowicz S, Roberts KA, Nestler JE.
Metformine reduces early pregnancy loss in polycystic ovary syndrome
(abstract no. P2-147). In: Program and abstracts of the 83rd Annual Meeting
of the Endocrine Society, Denver, CO. 2001:384.
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