Weight reduction programs designed for a modest weight loss (5%–10%) with the
incorporation of fitness are effective in reducing metabolic disease, cardiovascular
risk, and improving ovulatory potential.
40 A 5% to 10% weight loss in E.F. would be
9 to 18 lb. Diet modification and exercise are the most efficient, cost-effective, and
safe ways to produce weight loss and improve the endocrine and metabolic
40,44 Weight reduction should be considered first-line therapy in
all overweight or obese women with PCOS, and this should be recommended for
IMPACT OF WEIGHT LOSS IN POLYCYSTIC OVARY SYNDROME
A minimum 5% weight loss has consistently demonstrated restoration of regular
menstrual cycling and ovulation in overweight and obese women with PCOS.
When lifestyle modification is implemented, free testosterone concentrations
decrease, but clinical outcomes of acne and hirsutism are not often reported.
Obesity in PCOS is associated with a higher risk of developing endometrial cancer,
but very limited evidence exists to determine the impact of weight loss on the
incidence of endometrial cancer.
15 Studies of weight loss in women without PCOS
indicate a 25% to 50% reduced risk of endometrial cancer, so it is logical that
addressing weight reduction may lower that risk as well.
Program trial demonstrated a 53% prevalence of metabolic syndrome; the incidence
of this was reduced 41% in the lifestyle modification group.
significantly better than treatment with metformin. Studies specifically evaluating
cardiovascular improvements with weight loss in women with PCOS are limited, but
improvements in dyslipidemia and insulin sensitivity have been noted.
No single diet has been proven to be ideal for women with PCOS. A diet low in
saturated fat and high in fiber from mostly low-glycemic-index carbohydrate foods
may, however, be suitable and is recommended.
classification of carbohydrates based on the blood glucose response during 2 hours.
Low-glycemic index foods include bran cereals, mixed grain breads, broccoli,
peppers, lentils, and soy. High-glycemic index foods, or those that should be
minimized, include white rice and bread, potatoes, chips, and foods containing
simple sugars (e.g., juice). It has been shown that in women with PCOS, oral glucose
intake causes larger fluctuations in plasma glucose, increased hyperinsulinemia, and
stimulated adrenal steroid secretion; protein was found to be a preferred nutrient
52 The composition of a diet should be individualized to promote
adherence and achieve specific goals.
Exercise is a key component in the attainment and maintenance of weight loss.
Exercise with muscle strengthening improves insulin sensitivity.
Heart Association recommends 150 minutes/week of moderate exercise or 75
minutes/week of vigorous exercise.
53 E.F. should continue to eat a healthy diet. A diet
consisting of low saturated fats, high fiber, and foods with a low glycemic index
should be encouraged. E.F. should increase her exercise to at least 75 minutes/week
for at least 3 days of the week. If she is going to continue walking as her exercise, she
should walk at a brisk pace. Titrating her time to a goal of exercising 60 minutes
daily will help her lose weight.
appropriate to recommend for E.F.?
Several different pharmacologic options could be recommended to E.F (Table 50-
1). A combined oral contraceptive (COC) will address her concerns about irregular
menstruation, hyperandrogenism, and pregnancy prevention. An insulin sensitizer
would improve her menstrual irregularity and possibly reduce her hirsutism and
acne, but it does not address her desire to prevent pregnancy. An antiandrogen, such
as spironolactone, would address only hyperandrogenism, and other agents would
have to be used concurrently to address pregnancy prevention and other hormonal
and metabolic alterations in PCOS.
Estrogen–progestin combination therapy with a COC is the treatment of choice for
women seeking regularity in menstrual cycles and relief from hyperandrogenic
symptoms (see Chapter 47, Contraception, for a list of possible therapies). The
estrogen component suppresses LH, resulting in a reduction of androgen production,
and increases hepatic production of SHBG, thereby reducing free testosterone. The
progestins in various COCs possess variable androgenic effects, so the choice of the
COC may be considered to minimize androgenic exposure. The potential effects of
COCs on insulin resistance, glucose tolerance, and lipids have been debated, do not
appear to increase metabolic risk, and should be considered when choosing a
4,54–56 Caution should be used in those who have insulin
resistance, a high propensity to develop type 2 diabetes, or abnormal lipid profiles.
Combined oral contraceptive therapy in PCOS should be initiated with a
formulation that contains a low dose or very low dose of estrogen (≤35 mcg of
ethinyl estradiol) and a progestin with low androgenic or antiandrogen properties.
Most COCs manufactured today have low or very low estrogen doses. Desogestrel
and norgestimate are progestins with low androgen potential, and drospirenone is an
antiandrogen. A COC containing ethinyl estradiol and desogestrel would prevent
pregnancy, improve menstrual cycle regularity, and reduce E.F.’s signs of
hyperandrogenism (hirsutism and acne). If E.F. desired monthly cycles, she could
take the typical 21/7 regimen (21 days active pill, 7 days inactive pill) or a 24/4
regimen (24 days active pill, 4 days inactive pill). Although not specifically
evaluated in women with PCOS, a monophasic regimen may also be prescribed using
extended cycles of 84 or even 365 days. Extended regimens reduce the number of
cycles/year while providing contraception. Regardless of the COC selected, one of
the long-term benefits is that her risk for endometrial cancer would be reduced by
50%, even up to two decades after discontinuation.
options for E.F. include 30 to 35 mcg of ethinyl estradiol and a low-androgenic or
nonandrogenic progestin such as drospirenone or desogestrel. If she would like to
have her menstrual cycle monthly, she should take 21 active pills followed by 7
inactive pills. If she does not desire to have her menstrual cycle, then taking
continuous active pills in an extended (daily) manner is most appropriate. This
therapy would address her concerns of menstrual irregularity, contraception,
hirsutism, and acne. She should continue therapy for as long as she desires
contraception and minimization of the androgenic effects of PCOS.
E.F. if she considers this COC to be intolerable?
Selected Treatment Options for Polycystic Ovary Syndrome (PCOS)
Action Effective Dose Side Effects
Menstrual cyclicity Creates withdrawal
Biguanide (metformin) Impaired glucose
Hirsutism, acne Inhibits androgens
Ovulation induction Increases GnRH
increase to 150 mg gastrointestinal
Ovulation induction Blocks estrogen
FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.
Metformin inhibits hepatic glucose output, providing lower insulin concentrations
and reducing androgen production in the ovary. Metformin also appears to influence
ovarian steroidogenesis directly.
60,61 Metformin is primarily used for IGT or T2D
related to PCOS. Metformin has minimal effectiveness for hirsutism or acne and was
found to have no benefit improving rate of miscarriage, fertility, or live-birth rates in
Its routine use for treatment of infertility is not
In a Cochrane systematic review comparing COCs and metformin,
metformin demonstrated a reduction in fasting insulin and triglyceride levels
compared to oral contraceptives, but greater improvement in menstrual pattern and
serum androgen levels was observed with COCs.
The most commonly used and most effective dose of metformin in PCOS is 500 mg
orally 3 times daily (TID). It should be titrated slowly to this effective dose; doses
up to 2,000 mg daily or 2,550 mg daily may be necessary for individual
circumstances. The gastrointestinal (GI) side effects of diarrhea, nausea, vomiting,
and abdominal bloating are usually transient and dose-related, and can be minimized
by taking with food instead. An estimated glomerular filtration rate (eGFR) should be
calculated at least annually in women using metformin because it is contraindicated if
eGFR is <30 ml/min/1.73 m2 and not recommended if eGFR is 30–45 ml/min/1.73
Although frequently used, antiandrogens do not have FDA-approved uses for the
treatment of female hirsutism or acne in the United States. Spironolactone is
commonly prescribed to women for hirsutism. Drospirenone (a derivative of
spironolactone), found in COCs has antiandrogenic properties and has also been
evaluated in the long-term treatment of hirsutism.
64 Finasteride has been used for
female hirsutism, but its lack of specificity for type I 5α-reductase in the
pilosebaceous unit and toxicity may make this a suboptimal treatment choice.
Flutamide is effective for hirsutism, but it is not used because of hepatotoxicity.
Eflornithine hydrochloride has been approved for topical use in treating facial
hirsutism, but has not been well studied in women with PCOS. Electrolysis and laser
treatments may be acceptable physical approaches to hair removal for women with
Spironolactone acts by competitively inhibiting dihydrotestosterone (DHT) from
however, it takes 6 to 9 months for improvement.
65 Spironolactone may be associated
with possible teratogenicity (feminization of the male fetus), so it is prudent to advise
women to avoid pregnancy for at least 4 months after the discontinuation of
spironolactone. It is recommended that spironolactone be used with a COC to avoid
teratogenicity, as well as the side effect of polymenorrhea (more frequent menses)
when used as monotherapy. Spironolactone in combination with a COC would also
improve hormonal and metabolic manifestations of PCOS as well. The usual
effective spironolactone dose is 50 to 100 mg orally twice daily for 6 to 12 months.
Serum potassium and renal function should be monitored because this aldosterone
antagonist can cause hyperkalemia. Furthermore, spironolactone should not be used
with a COC containing drospirenone because of a potential risk for hyperkalemia.
Finasteride is a type II 5α-reductase inhibitor, which decreases the conversion of
testosterone to DHT. It provides an approximate
30% reduction from baseline for hirsutism. Compared with spironolactone,
finasteride is as or less effective in women with hirsutism.
orally daily typically takes 6 months for clinical improvement. It is critical to avoid
pregnancy while taking this drug owing to the potential teratogenic effect of abnormal
genitalia in the male fetus. Finasteride should not be touched or handled by women
who are or may be pregnant. This danger limits the usefulness of finasteride in
women with PCOS because most are of childbearing age or desire pregnancy.
E.F. should be encouraged to continue her COC for at least 3 months as most COC
side effects resolve within 3 months of use. If E.F. decides that the side effects from
the COC are intolerable, an appropriate recommendation for E.F. would be
spironolactone 50 mg orally daily. She should continue this therapy for as long as she
desires the benefits of this therapy, but it will not provide contraception. E.F. should
ensure proper contraception is used while taking spironolactone to avoid
for ovulation induction should be used in E.F. and why?
Anovulation or oligo-ovulation in women with PCOS is usually first treated with
diet, exercise, and weight reduction. Weight loss improves pregnancy rates and
reduces miscarriage rates in women with PCOS. E.F. has been successful at losing
weight and now must consider agents for ovulation induction.
AGENTS FOR OVULATION INDUCTION
Clomiphene citrate induces ovulation via an antiestrogenic effect on the
hypothalamus. GnRH secretion is increased, which increases LH and FSH
production. The increase in FSH concentrations causes appropriate follicle
development and estrogen secretion, which produces a positive feedback on the
hypothalamic–pituitary system to create a LH surge for ovulation.
The usual initial dose of clomiphene citrate is 50 mg orally daily for 5 days,
started on day 5 after a spontaneous or progestin-induced menses. The clinician must
determine whether ovulation occurs with each cycle through laboratory testing,
ultrasound monitoring, or both. If ovulation does not occur, the dose can be increased
by 50 mg orally daily up to 150 mg orally daily; however, doses greater than 100 mg
orally daily for 5 days are not recommended by the manufacturers.
can be administered as early as 30 days after the previous cycle as long as pregnancy
has not occurred. If conception does not occur, women can use clomiphene for three
to four cycles before considering another regimen. Long-term cyclic therapy is not
recommended beyond a total of six cycles because of potential ovarian cancer risk.
Most women respond to clomiphene citrate within three to four ovulatory cycles, but
5% to 10% have demonstrated clomiphene resistance and need to consider other
67 For women who are clomiphene citrate-resistant, dexamethasone can be
used in conjunction with clomiphene or an aromatase inhibitor can be used (e.g.,
letrozole, anastrozole) as an alternative for infertility in PCOS.
Letrozole is an aromatase inhibitor which blocks estrogen synthesis to directly affect
hypothalamic–pituitary-–-ovarian function and increase pregnancy rates. Potential
advantages of letrozole over clomiphene citrate include more physiologic hormonal
symptoms, and more rapid clearance which reduces the chances of periconceptional
In a study of 750 women with PCOS, letrozole or clomiphene was
provided for up to five cycles whereas ovulation and pregnancy were evaluated.
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