Polycystic ovarian
syndrome (PCOS), also known as Stein-Leventhal syndrome, is a common
gynecological disorder characterized by hypergonadotrophism, hirsutism,
obesity, oligomenorrhea and commonly associated with infertility.1
PCOS is a complex clinical picture and presents a multifaceted etiology
related to imbalance of the hypothalamic-pituitary-adrenal (HPA) axis,
thyroid involvement and metabolic syndrome (insulin resistance).1 There
is substantial evidence that PCOS should no longer be considered purely
a gynecological disorder, but rather a complex endocrine disorder.2
PCOS affects approximately 5 to 10% of women of reproductive age and
is one of the most common causes of anovulatory infertility.2 Menstrual
disruption typically manifests in PCOS, ranging from oligomenorrhea to
amenorrhea.
Etiology
Despite the extensive investigations, the etiology of PCOS remains
poorly understood. The most recent knowledge indicates that abnormal
insulin response to glucose stimulus is a key underlying factor in
PCOS. 2,3 Other etiological factors include derangement of the sympathetic
nervous control of the ovaries,4 estrogen dominance and elevated
androgens. Some of the literature suggests a genetic susceptibility
to insulin stimulation of androgen secretion, blocking follicular
maturation.
Insulin Resistance
PCOS and insulin resistance are intimately related endocrine disorders.
The most common causes of insulin resistance are obesity, poor diet
and stress. Hyperinsulinemia is not a characteristic of hyperandrogenism
in general, but is uniquely associated with PCOS.2
In obese women with PCOS, 30 to 40% of these have impaired glucose
tolerance or diabetes. However, women with ovulatory hyperandrogenism
can present with normal insulin and glucose tolerance,1,2 indicating
additional factors are potentially involved in the etiology.
Elevated Androgens
The ovarian and adrenal glands of women with PCOS are usually the sites
of production of elevated androgens. It is postulated that these
women have a hyperactive production of CYP17 enzyme, which is responsible
for forming androgens in the ovaries and adrenals (from DHEA-S).2
Elevated total and free testosterone correlate with the typically
elevated LH levels. Serum total testosterone is usually up to twice
the normal range (20 to 80 ng/dL). High androgen levels in the ovary
inhibit FSH, thereby inhibiting development and maturation of the
follicles.1,2
DHEA is found to be elevated in 50% of women with PCOS.2 The elevated
DHEA is due to stimulation by ACTH, produced by the pituitary in response
to stress. The excess DHEA then converts to androgens via adrenal metabolism,
which in turn contributes to the typical elevated androgen levels in
PCOS.
The skin and adipose tissue add to the complex etiology of PCOS. Women
who develop hirsutism have the presence and activity of androgens in
the skin which stimulate abnormal patterns of hair growth. Aromatase
and 17-beta-hydroxysteroid activities are increased in the fat cells
and peripheral aromatization increases with body weight. The metabolism
of estrogens by way of 2-hydroxylation and 17-alpha-oxidation is decreased.
Estrogen levels increase as a result of peripheral aromatization of
androstenedione. This cascade results in a chronic hyper-estrogen production
(estrogen dominance).2
Hirsutism occurs in 70% of women with PCOS in the US, as opposed to
only 10 to 20% of Japanese women diagnosed with PCOS.3 This may be
explained by the genetically determined differences in 5-alpha-reductase
activity between different cultures, or from a holistic standpoint,
may reflect differences in endocrine behavior in accordance with local
diet and levels of physical fitness.
Estrogen Dominance
The hypothalamic-pituitary axis imbalance can contribute significantly
to the etiology of PCOS. The result of increased gonadotrophin releasing
hormone (GnRH) output causes an elevation in the pulsatile output
of LH and results in an elevated LH to FSH ratio (typically 2:1 respectively).2,5
FSH is not increased as a result of elevated LH in this case, likely
due to the hypothalamus responding via negative feedback to the already
chronically elevated estrogen levels.
About 25% of PCOS patients exhibit elevated prolactin,1,2 known as
hyperprolactinemia. Hyperprolactinemia results from abnormal estrogen
negative feedback via the pituitary gland. Elevated prolactin can in
turn contribute to elevated estrogen levels.
PCOS Holistic Diagnostic Criteria
Menstrual
irregularity
· Eight or fewer menstrual
cycles per year
· Unpredictable menstrual cycles
· Amenorrhea for longer than 4 months in the absence of pregnancy or
menopause
· Infertility
· History of ovarian cysts
· Irregular bleeding
· Excessive or heavy bleeding
Skin complications
· Adult acne
· Severe adolescent acne
· Cystic acne on face, neck, back shoulders
· Hirsutism with excessive hair on face, body, upper lip, chin, neck,
abdomen
· Thinning of the head hair or male pattern balding
· Acanthosis nigricans: discoloration or darkening of skin (may be in
patches) around neck, groin, under arms, skin folds or skin tags
(see later)
Insulin resistance
· Weight gain, especially around trunk (apple body shape or android body
shape, especially after the age of 30 years)
· Dysglycemia
· Difficulty losing weight
· Family history of diabetes or menstrual irregularity
Obesity is found in 50% of patient with PCOS.1,2,5 The body fat
is usually located centrally around the trunk. A higher waist to hip
ratio indicates an elevated risk of cardiovascular disease and diabetes.1
Insulin resistance and metabolic syndrome are commonly seen in PCOS
patients and insulin resistance is now recognized as a risk factor
for the development of diabetes mellitus type.2 Approximately
one-third of obese PCOS patients have impaired glucose tolerance
and up to
10% have diabetes mellitus type 2.2 Acanthosis nigricans, a condition
in which the vulva develops thickened, pigmented velvety lesions,
is
considered a marker of insulin resistance in women with hirsutism. These lesions
can also be found on the nape of the neck, inner thigh and below
the
breast. Women with severe insulin resistance can develop HAIR-AR
syndrome consisting of hyperandrogenism (HA), insulin resistance (IR) and Acanthosis
nigricans (AR).1,2 These women will have elevated testosterone
(>150
ng/dL) and fasting insulin levels of greater than 25 mIU/dL. Insulin
alters steroidogenesis (independent of gonadal production) in PCOS,
as insulin and insulin-like growth factor receptors are located within
the ovarian tissue.2
Associated with impaired glucose tolerance is the abnormal lipoprotein
profile that can be seen commonly in patients with PCOS. The typical
PCOS lipoprotein profile includes:
· Elevated total cholesterol
· Elevated triglycerides
· Elevated low density lipoproteins (LDL)
· Low high density lipoproteins (HDL)
· Low apoprotein A-12
The culmination of these factors leads to a marked elevation in cardiovascular
risk for the PCOS patient. Another metabolic observation that puts
these women at higher cardiovascular risk is the incidence of impaired
fibrinolysis, shown by elevated circulating levels of plasminogen activator
inhibitor. This is associated with atherosclerosis and hypertension.
When these factors are combined, PCOS women are at much higher risk
of hypertension, atherosclerosis, and exhibit a seven-fold risk of
myocardial infarction.2
Recommended Naturopathic Hormonal Evaluation
· Salivary
Adrenal Stress Index, including ACTH
· Salivary or serum expanded female hormonal panel, including testosterone
and LH to FSH ratio
· Glucose tolerance test
· Thyroid panel
· Blood lipid profile
Typical Hormonal Disturbances Associated with PCOS Diagnosis include:
· LH is elevated while FSH is usually low at a ratio of 2:1
· Progesterone can be low
· Sex Hormone Binding Globulin (SHBG) is usually low
· Androgens such as testosterone and DHEA-S are usually elevated
Conventional Treatment Approaches
The conventional treatment for PCOS
is dependent on the patient's
desired goal of either menstrual regularity in order to achieve pregnancy,
or menstrual regularity for contraception. Some women seek treatment
for the removal of excessive male hair growth patterns, such as increased
facial hair (common to women with PCOS and elevated androgens). Women
are currently being treated according to their presenting clinical
symptoms, including irregular menses, hirsutism and infertility.1,2,5
Irregular Menses
A combined oral contraceptive pill is commonly used to regulate the
menses. By both increasing the levels of sex hormone binding globulin
(SHBG) and decreasing androgen secretion, this can reduce elevated
free testosterone activity. The combined pill worsens insulin resistance
and if the patient falls into the categories of being overweight
or obese, this therapy is relatively contraindicated.1,2
Hirsutism
Hirsutism is addressed with the administration of the anti-androgens
cyproterone acetate or spironolactone. The action of these drugs
is to inhibit the binding of dihydrotestosterone (DHT) to the receptors
at the hair follicle site.6
Infertility
Clomiferine citrate is suggested to women with PCOS who are diagnosed
with fertility challenges. This drug induces ovulation and does increase
risk of multiple pregnancies.6 It acts by inhibiting the
estrogen negative feedback at the hypothalamus, thus enhancing the
pituitary's
production of FSH.
Other Pharmaceutical Medications
Other pharmaceutical medications which can be prescribed for PCOS include
medroprogesterone acetate, gonadotrophin releasing hormone agonists,
glucocorticoids, ketoconszole, flutamide, finasteride and metformin.
Overview of Botanical Protocol
Strong evidence supports the current hypothesis that the underlying
cause of PCOS is due to insulin resistance (a decreased peripheral
sensitivity to insulin), hence managing this aspect becomes the most
important feature for the phytotherapist. The exact mechanisms for
insulin resistance are not yet known within the conventional medical
community, however the holistic practitioner finds that insulin resistance
has a high correlation to a diet high in refined carbohydrates coupled
with a poor adrenal glycemic counterbalance. As the HPA axis becomes
weakened (as a result of chronic stress), insulin sensitivity becomes
heightened, adversely affecting the ovaries and thyroid. Elevated
insulin and insulin-like growth factor have an effect in stimulating
androgen production from the adipose tissue, ovaries and adrenals.
Under chronic stress, excess cortisol is produced from the adrenal
glands, triggering the release of elevated levels of prolactin and
a sympathetic nervous system response.4 Prolactin has an inhibitory
effect on the production of FSH and elevates the production of LH,
worsening the scenario for women with PCOS. It is essential that
the adrenals are well supported at a functional level with herbal
adrenal tonics such as Glycyrrhiza glabra and supported by adaptogens
such as Withania somnifera.
The first step in restoring ovarian function and a normal menstrual
cycle in a PCOS patient is to break the pattern of hyperinsulinemia
with a combination of diet and lifestyle strategies. Implementing a
low refined carbohydrate diet and exercise is essential for a truly
successful protocol.
Primary Herbs
Paeonia lactiflora (White peony)
Paeonia lactiflora has been used for gynecological conditions by
both Chinese and Western herbalists, and is used by Western herbalists
for
PCOS, hyperprolactinemia, endometriosis, ovarian failure and androgen
excess. Paeonia has been shown to positively influence low progesterone,
reduce elevated androgens (testosterone) and acts to modulate estrogen
and prolactin.7 In vitro, the active constituent paeoniflorin has
been shown to affect the ovarian follicle by its action on the
aromatase
enzyme.8 Aromatase is important for follicle maturation, ovulation
and corpus luteum function, steroid hormone synthesis and the regulation
of the conversion of androgens to estrogens. The biofeedback in
the pituitary and hypothalamus rely on aromatase to regulate prolactin
and GnRH. The daily dose for Paeonia is 4.5 to 9 mL of a 1:2 dried
plant extract.9
The traditional Chinese/Kanpo formula known as Shakuyaku-Kanzo-To
or TJ-68, which is a decoction of Glycyrrhiza glabra and Paeonia
lactiflora,
has been the subject of a number of clinical trials, all of which
demonstrate activity in the hormonal regulation of androgens. In
one trial involving
eight women with hyperandrogenism and oligomenorrhea, the formula
was given for 2 to 8 weeks. This combination regulated the LH to
FSH ratio.
Over this period of time, serum testosterone levels decreased to
less than 50 ng/dL and this resulted in seven of the eight women
ovulating
regularly.10
Another trial involved 20 women diagnosed with PCOS. The formula
was successful in lowering testosterone in 90% of the women, of
which 25%
went on to conceive.11 It is suggested that it acts directly on
the ovary, increasing the activity of aromatase, which promotes
the synthesis
of estradiol from testosterone, thus lowering serum testosterone
levels. It also seems to regulate the LH to FSH ratio.12
Gymnema sylvestre (Gymnema)
Gymnema is a traditional Ayurvedic herb used as an antidiabetic, hypoglycemic,
lipid lowering agent and to support weight reduction. Gymnema possibly
has a tropho-restorative action of the beta cells of the pancreas.13
The plant part used as medicine is the leaf. Gymnema is well indicated
for PCOS, due to its insulin modulating activity and the added benefits
of reducing the elevated triglycerides associated with PCOS. Key
constituents of Gymnema include saponins, especially the gymnemic
acids. Gymnemic acid suppresses the sweet taste on the taste buds,
so if taken before food masks the sweet sensation. Gymnema has demonstrated
hypoglycemic activity in experimental models of diabetes and regulated
blood sugar in hyperglycemia. The mechanism of action also includes
the inhibition of glucose absorption in the intestine. The daily
dose of Gymnema is 3.5 to 11 mL of 1:1 liquid extract.9,14 Since
conventional medical models are focussing on pharmaceutical agents
such as metformin to control PCOS, Gymnema may prove to be one of
the most significant herbs in the treatment of the underlying factor
of insulin resistance.
Tribulus terrestris (Tribulus)
Tribulus is an endemic weed to many regions of the world, such as the
Mediterranean, India, China, South Africa and Australia and is commonly
known as puncture vine. The aerial parts, particularly the leaf,
are used for medicinal purposes in the Western tradition. As a result
of Bulgarian research, Tribulus has become a popular herb for the
treatment of female and male endocrine disorders.15 It acts as a
general tonic, aphrodisiac, estrogen modulator and androgen modulator
and is used to restore vitality, libido and reduce the physiological
effects of stress.9,11
The Bulgarian research has identified a unique steroidal saponin class
known as furostanol saponins, and extracts are standardized to contain
at least 45% of these saponins, calculated as protodioscin. The leaf
is noted to be higher in these unique saponins rather than the fruit
or root. Other active constituents include phytosterols and spirostanol
glycosides.
The tonic activities of Tribulus have been shown to act by intensifying
protein synthesis and enhancing the activity of enzymes associated
with energy metabolism. It increased iron absorption from the small
intestines and inhibited lipid peroxidation during stress. This leads
to more muscle strength and improved endurance and stamina.9
To ensure the desired clinical results, it is recommended to use only
the Bulgarian grown Tribulus standardized to 40% furostanol saponins.
It is not interchangeable with the Chinese or Indian Tribulus. The
daily dose of Tribulus corresponds to extracts containing furostanol
saponins as protodioscin at 300 mg to 400 mg per day. In PCOS it is
best used on days 5 to 14 of the menstrual cycle to restore menstrual
regularity. For more information on Tribulus, see the forthcoming review
which will be published in next month's Townsend Letter.
Vitex agnus-castus (Chaste tree)
Vitex is beneficial for ovulatory factors associated with PCOS, in
particular it has been shown to downregulate the production of excess
prolactin, a condition known as hyperprolactinemia.16 Vitex is also
postulated as having antiandrogenic properties.16 Hyperprolactinemia
is related to adrenal stress and hyperinsulinemia in PCOS. It is
well documented that the active constituents in Vitex demonstrate
a dopaminergic activity and dopamine inhibits the production of prolactin.
The dopaminergic compounds in Vitex have been identified as the diterpene,
including rotundifuran and 6ß,7ß-diacetoxy-13-hydroxy-labda-8,14-diene.
However, recent research is pointing to other phytochemicals which
may have this activity.17 Other constituents of Vitex include essential
oils, flavonoids (such as casticin) and iridoid glycosides (including
aucubin and agnuside).9,14
Hyperprolactinemia, or the more subtle condition of latent hyperprolactinemia,
are amongst the most frequent causes for cyclical disorders, including
corpus luteal insufficiency. This can lead to premenstrual syndrome
(PMS) and progesterone deficiency, secondary amenorrhea and premenstrual
mastalgia.18 In an uncontrolled study, Vitex reduced elevated prolactin
levels in 80% of 34 women with hyperprolactinemia at a dosage of 30
to 40 mg per day for 1 month and improved symptoms of a variety of
menstrual disorders, including secondary amenorrhoea, cystic hyperplasia
of the endometrium, deficient corpus luteum function, metrorrhagia,
polymenorrhea and oligomenorrhea.9
Vitex reduced the thyroxin releasing hormone (TRH)-induced prolactin
release (essentially a pituitary-thyroid axis problem), normalized
shortened luteal phases, corrected luteal phase progesterone deficiencies
and reduced PMS symptoms in women with luteal phase defects due to
latent hyperprolactinemia.9
Vitex should be considered first line botanical therapy for hyperprolactinemia
and given for the duration of at least 3 to 6 months. In herbal writings
Vitex is often attributed to increasing LH, which is not desirable
in PCOS. However, clinical experience has shown that it is valuable
in PCOS, especially when combined with other herbs, probably because
of its action in reducing prolactin. The daily dose of Vitex to is
1 to 4 mL of a 1:2 dried plant tincture or 500 to 1000 mg of dried
berries daily.9 It is best taken as a single dose in the morning.9
In PCOS it is best combined with Tribulus and Paeonia.
Caulophyllum thalictroides (Blue cohosh)
Caulophyllum thalictroides is known by the common name of blue cohosh
and is native to North America. Within traditional use among the
Native North Americans it was used by women as a remedy for amenorrhea
and profuse menstruation, both of which are common features of PCOS.
It is particularly useful to bring on the menses in PCOS. It has
action as a uterine and ovarian tonic and pelvic anti-inflammatory.
The known constituents of Caulophyllum root include glycosides, caulosaponin
and caulophyllosaponin, which are known to stimulate the uterus.
Other identified constituents include N-methylcystine, taspine and
thalictroidine.9 The daily dose is 1.5 to 3 mL of 1:2 dried plant
extract.9
Sample PCOS Formula
Vitex agnus-castus |
1:2 |
12.5 mL |
Glycyrrhiza glabra |
1:1 |
12.5 mL |
Paeonia lactiflora |
1:2 |
25 mL |
Gymnema sylvestre |
1:1 |
25 mL |
Schisandra chinensis |
1:2 |
25 mL |
|
|
100 mL |
Dose: 15 mL per day or 5 mL three times daily |
In a case of a PCOS patient with amenorrhea, include Caulophyllum
thalictroides at a dose of 2 mL per day to help induce the menses.
When a cycle has been initiated, change to Tribulus concentrated extract,
equivalent to furostanol saponins (as protodioscin) 300 to 400 mg per
day on days 5 to 14 of the cycle to ensure cyclic regularity.
Dietary Modification
A review of the extensive literature specific to lifestyle factors
in PCOS demonstrates that an essential treatment strategy for ameliorating
the symptoms of PCOS and resolving the underlying metabolic derangements
is the implementation of a low carbohydrate diet. This will tightly
control blood sugar levels and resultant insulin production. High
levels of insulin result in high levels of triglycerides and low
levels of high density lipoproteins, which puts these patients into
a high cardiovascular disease risk category. Modulating the diet
not only helps the female endocrine cycle, but also serves as preventative
medicine against these cardiovascular risk factors. As the insulin
levels normalize, this will also improve circulating levels of SHBG,
therefore limiting the problematic effects of free androgens on the
menstrual cycle.2,6
Women with PCOS are urged to lose 5 to 10% body weight using a moderate
protein, low refined carbohydrate diet. When this approach was taken
in one clinical trial, 10 of the 11 subjects resumed a normal cycle
within 10.5 months.2 In a similar study, such weight loss restored
ovulation in 60 out of 67 previously anovulatory women.3 The dietary
profile should include approximately 30% good quality fats, 40% protein
and 30% complex carbohydrates.1,2,19 Literature suggests establishing
an energy efficient diet of 1000 to 1500 kcal per day. It is recommended
to avoid alcohol, caffeine, smoking and psychosocial stressors. Gymnema
is helpful in reducing carbohydrate and sugar cravings, and therefore
improving compliance with dietary changes.9
Exercise
Implementing an exercise regime of approximately 30 minutes per day
will assist weight loss and improve the endocrine regulation of stress.
Case History
Female patient aged 34 presented with irregular menses and was considering
attempting to become pregnant. She had been diagnosed with PCOS for
the past 2 years. Up until 6 months prior to her consultation, she
had taken the oral contraceptive in combination with Levoxyl, but
suffered side effects of heightened emotional lability from these
drugs.
Her menstrual cycle varied in length anywhere from 50 to 70 days and
she experienced mid-abdominal cramping for 24 hours prior to the onset
of her menses. The flow was medium to light and lasted for 4 to 5 days,
dark red in color, starting with brown spotting for 12 to 18 hours.
She had occasional menstrual clots, stringy and lumpy in nature.
Her skin was badly affected by the PCOS and she experienced painful,
deep cystic acne on her face, chest and back, which was worse for up
to a week before the onset of each period. She had taken two courses
of isotretinoin (Accutane) within the past 5 years and regularly used
a tetracycline for treatment of her acne. Breast tenderness was an
uncomfortable premenstrual feature.
She had gained 23 pounds over the past 3 years, which she had difficulty
losing, despite exercise on a regular basis. She did however eat a
high carbohydrate diet and craved sugar intensely.
She was a shift worker in a high stress and responsibility occupation
and fatigue was a daily experience.
She was taking prescribed thyroid hormone (thyroxine) for Hashimoto's
thyroiditis, diagnosed 4 years prior. At the same time she was diagnosed
as having secondary osteoporosis. Recent evaluation showed her spinal
density indicated osteopenia, her femoral density indicated osteoporosis
and total hip density indicated severe osteopenia.
Additional Assessment
Hormonal evaluation showed a typical pattern of a 2:1 LH to FSH ratio,
with elevated testosterone and hyperlipidemia.
Treatment Protocol
Vitex agnus-castus |
1:2 |
12.5 mL |
Glycyrrhiza glabra |
1:1 |
12.5 mL |
Paeonia lactiflora |
1:2 |
20 mL |
Gymnema sylvestre |
1:1 |
20 mL |
Echinacea spp. root |
1:2 |
10 mL |
Schisandra chinensis |
1:2 |
20 mL |
|
|
100 mL |
Dose: 8 mL twice daily |
Additionally:
· Tribulus concentrated extract,
equivalent to furostanol saponins (as protodioscin) 300 to 400 mg per
day on days 5 to 14 of the cycle to
ensure cyclic regularity.
· Fucus vesiculosus 1:1, 10 mL twice daily.
Rationale
Vitex agnus-castus was indicated for
the hormonal imbalance and hyperprolactinemia, often resulting in the
symptom of premenstrual breast tenderness.
A combination of Glycyrrhiza glabra and Paeonia lactiflora were included
into the formula to mimic the synergy of these plants in TJ-68 to
reduce elevated testosterone and induce ovulation. Gymnema sylvestre
was included in the formula to treat the insulin resistance and hyperlipidemia
and assist with reducing associated carbohydrate cravings. Echinacea
spp. root was an important inclusion for the autoimmune mediated
hypothyroid condition. Echinacea serves as an immune modulator in
this case. Schisandra chinensis was included in the formula to provide
liver support, in particular to improve the liver's ability
to conjugate sex hormones, and assist in reducing the circulating
levels of testosterone and estrogen. Tribulus was selected to ensure
a healthy follicular phase of the cycle and as an androgen modulator.
Fucus vesiculosus was indicated for thyroid support as a plant source
of iodine and is traditionally recommended by herbalists to assist
with weight loss associated with hypothyroidism.
Conclusion
After 5 months on the herbal protocol,
the patient's cycle had
regulated to a 32 day cycle, with a consistent 15 day follicular phase
and a 17 day luteal phase. Problematic symptoms such as mastalgia,
acne and hirsutism diminished significantly during the 5 month program.
The lipid profile has improved to within normal ranges, and with the
inclusion of the combined regimen of Gymnema, dietary modification
(low carbohydrate diet) and exercise, she lost a total of 12% body
weight in the 5 months. She went on to begin a full preconception health
care program and became pregnant in her second month.
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