PCOS
Polycystic Ovary Syndrome

Author: Elisa Picardo
Date: 03/11/2008

Description

LA SINDROME DELL'OVAIO POLICISTICO (PCOS) di Picardo e Mitidieri

La malattia è caratterizzata da ovaie ingrandite, policistiche: il riscontro più comune è un ovaio bianco, liscio, sclerotico con una capsula ispessita , cisti follicolari multiple in vari stadi di atresia, iperplasia della teca e dello stroma. Rappresenta la più frequente affezione cronica della ciclicità mestruale (5-10% tra le donne in età feconda).
Sul piano clinico è caratterizzata da oligo-amenorrea, anovulazione cronica, sovrappeso (obesità), androgenizzazione cutanea e sul piano biochimico da iperandrogenismo ed iperinsulinemia.
Ancora ignota la causa prima, se ne sta delineando la patogenesi.

Ecografia di ovaio policistico

STORIA NATURALE
1. Soggetti tendenti all’obesità già nell’infanzia
2. All’adrenarca (sviluppo dell’attività della reticolare del surrene produttrice di androgeni (DHEA) intorno agli 8-10 anni, può essere oggettivata dalla comparsa del pelo ascellare) manifestano i primi segni di iperandrogenismo e un’aumentata frequenza di cisti follicolari.
3. Al menarca hanno elevata frequenza di acne ed irsutismo
4. Alla pubertà hanno oligomenorree con cicli anovulatori ed irsutismo
5. In età adulta hanno irregolarità mestruali e iperandrogenismi evolutivi, tendenza ad obesità ed aumentato rischio di carcinoma endometriale
6. Al climaterio hanno aumentata tendenza all’obesità e aumentato rischio di adenoma endometriale.
7. Hanno una post-menopausa di solito normale (in qualche caso aumenta l’irsutismo).

Ipotetici meccanismi patogenetici della PCOS

QUADRO ENDOCRINO ANOVULATORIO E CICLO MESTRUALE: FSH ED LH
Le cisti sono follicoli che non hanno ovulato e sono entrati a far parte del compartimento stromale.
Nella PCOD ciò che conta non è tanto l’aspetto morfologico delle cisti, quanto il fatto che queste numerose cisti facciano parte dello stroma ovarico e siano quindi produttrici di androgeni. Gli androgeni hanno due funzioni: da una parte possono agire come tali e rendersi responsabili del corredo clinico ben noto, dall’altra possono essere convertiti in estrogeni per l’aromatizzazione periferica.

Meccanismo d’azione cellulare degli steroidi androgeni e delle molecole ad attività antiandrogena (in rosso)

La combinazione di elevati livelli di androgeni surrenali e di obesità conduce a un aumento della produzione extraghiandolare di estrogeni e quindi a un feedback positivo aciclico sull’LH e negativo sull’FSH. Ciò determina un rapporto LH/FSH plasmatico superiore a 2.
Si crea un circolo vizioso: atresia follicolare, quindi iperplasia stromale e tecale (prevale componente stromale su quella follicolare), quindi LH agisce su componente stromale stimolandola. Aumentano quindi testosterone (fT) ed androstenedione (A4) totali; entrambi hanno la proprietà di essere aromatizzati ad estrogeni in periferia, ed in particolare il testosterone in estradiolo (E2) e l’androstenedione in estrone (E1).

Nella PCOD con eumenorrea si ha un lieve aumento della risposta insulinica al carico da glucosio rispetto ai controlli, nella PCOD con oligomenorrea invece c’è un’elevatissima risposta insulinemica al carico. Tanto più elevata è l’insulinemia tanto più elevata è l’insulino-resistenza.

Meccanismi potenziali con cui l’insulina può aumentare secrezione e attività biologica degli androgeni

DIAGNOSI
La diagnosi di PCOD deve essere sempre clinica e si basa sulla coesistenza di anovulazione cronica e di vari gradi di ipeandrogenismo.
I criteri per la diagnosi ecografica sono molto restrittivi e si incontrano raramente:
• volume ovarico > 13-17 ml, soprattutto se diametro max > 4.5 cm
• presenza di 10 o più cisti, con diametro variabile fino a 2 cm
• ipercecogenicità e aumento di spessore della capsula ovarica
• aumento dello stroma

Iperplasia della corteccia ovarica con multipli follicoli

TERAPIA
La terapia della PCOS tende a interrompere il circolo vizioso: correggendo il disordine mestruale e/o inducendo la fertilità:
1. Un progestinico
2. Un estroprogestinico, la pillola, oppure un sequenziale EP
3. Indipendentemente dal ciclo, possiamo usare lo spironolattone (Aldactone), diuretico risparmiatore di K, per ridurre il peso.
4. Un altro farmaco è la finasteride (Prostide), anti-androgeno comunemente usato nel carcinoma prostatico.
5. Un’altra possibilità è la terapia chirurgica, che è la resezione cuneiforme dell’ovaio, di cui in passato è stato fatto largo uso, poi non si è più fatta, oggi viene rivalutata. Non si fa più in laparotomia, ma in laparoscopia, e consiste in uno scraping più che in una resezione cuneiforme. E’ molto importante in quei casi in cui ci sia un notevole ispessimento della capsula, tale per cui l’uovo non riesce fisicamente a “rompere” la superficie.

DIAGNOSI DIFFERENZIALE
La diagnosi differenziale va posta con l’ovaio multifollicolare (MFO) che dal punto di vista morfologico è molto simile, ecograficamente identico alla PCOD, ma il volume ovarico medio è più basso e soprattutto mancano le stigmate ormonali della PCOD.
L’MFO è una patologia molto meno grave per la paziente e non c’è il rischio che peggiori con il tempo.

Items

PolyCystic Ovary Syndrome and insulin resistance

Comments

2013-02-24T08:08:48 - Elena Cerino

A diet rich in carbohydrates as concause of PCOS

- Elena Cerino -

PCOS has a multifactorial etiopathogenesis.

It has a genetic component (familiarity is documented in the 50% of cases ), even though the exact mechanism of transmission isn’t known yet; and an environmental one.

With regard to the environmental component, dietary habit is extremely important.

In fact, a diet rich in carbohydrates, particularly simple carbohydrates, may lead to a chronic increase of insulin levels in the bloodstream, which is going to feed the PCOS vicious circle, and that will lead to develop a diabetes mellitus type II in the 20% of cases.

When insulin levels are sufficiently high over a prolonged period of time (due to alimentation), it causes the body’s own sensitivity to the hormone to be reduced.
This represents a serious problem, because pancreas has to secrete a larger amounts of insulin to compensate and keep blood sugar at a normal level.
Obviously this comports an ulterior increase of circulating insulin levels, which becomes chronic.

This phenomenon is known as Insulin Resistance, it’s hardly reversible, and represents the main cause of Hyperinsulinemia.

High levels of insulin strongly affect the androgens secretion, overstimulating it.

More specifically, insulin:

• Has an effect directly on the ovarian theca cells, activating the Cytochrome P450c17, key enzyme in the synthesis of androgens.

• Magnifies the effect of the Luteinizing Hormone (LH) on the synthesis of androgens. Actually, it has been proved that the effect on the Ovary of both substances (LH and Insulin), is major than the simple sum of the two effects.

• Induces a decrease of the circulating SHBG (Sex Hormon Binding Globulin) levels. SHBG is a protein synthesized mainly by the liver, it binds the sex hormones circulating in the bloodstream and, as a matter of fact, its levels tend to decrease when high ones of insulin are present in the blood, therefore causing an increase of free testosterone.

• Can suppress the epathic synthesis of IGFP-1, therefore increasing the availability of IGF-1, another important regulator of ovarian androgen synthesis.

• Acts at the level of the Hypothalamus, tampering with the cyclic nature of the pulse generator, which leads to a positive feedback stimulation of LH, (increase of both frequency and width, of its secretory peaks) causing a further increase of its levels.

On the other hand, one of insulin’s effects has puzzled researchers.

In fact, insulin happens to up-regulate aromatase, the key enzyme in the synthesis of Oestradiol (an estrogen) from Testosterone, which of course would be expected to lead to a Testosterone decrease and an Oestradiol increase.

Only, we know that in patients affected by PCOS, this doesn’t happen, on the contrary, as already said they presents high levels of Testosterone, and low levels of estrogens.
So researchers came to the conclusion that aromatase must be inhibited in PCOS patients, therefore nullifying any positive effect insulin may have had on its up-regulation.

They suggested that PCOS follicles might contain an endogenous inhibitor of estrogen production.

To test this hypothesis, the Department of Obstetrics and Gynecology, Cedars-Sinai Research Institute/ University of California, School of Medicine, of Los Angeles conducted a study ( A mechanism for the suppression of estrogen production in polycystic ovary syndrome; Agarwal SK, Judd HL, Magoffin DA; 1996 ) in which granulosa cells from hyperstimulated women were cultured with increasing concentrations of follicular fluid (FF) from PCOS and normally cycling control women in the presence of androstenedione.

Follicular fluid from control women caused a small decrease (20%) in estradiol production.

PCOS FF caused a dose-related inhibition of estradiol production (60%), indicating that there was significantly more inhibitory activity in PCOS follicular fluid.

To determine whether abnormal androgen metabolism could play a role in inhibiting estradiol production in PCOS, they measured 5 alpha-androstane-3, 17-dione, a competitive inhibitor of aromatase activity, in serum and FF of control and PCOS women.

5 alpha-Androstane-3, 17-dione levels in serum were significantly elevated in PCOS. 5 alpha-Androstane-3, 17-dione levels were 1000-fold higher in PCOS FF than serum.

Moreover, FF levels were markedly higher in PCOS follicles than in normal dominant and cohort follicles.

Dose-response studies revealed that the concentration of 5 alpha-androstane-3, 17-dione present in FF from normal dominant follicles had little effect on estradiol production. In contrast, 5 alpha-androstane-3, 17-dione levels in PCOS FF inhibited estradiol production by 75%.

These data support the hypothesis that PCOS follicular fluid contains one or more endogenous inhibitors of aromatase activity and suggest that abnormally high 5 alpha-androstane-3, 17-dione levels in PCOS follicular fluid may be an important inhibitor of estradiol production.

It’s all the more obvious then, that having PCOS a multifactorial etiopathogenesis, whose genetic component is still largely unknown, and for which we don’t know any applicable countermeasure yet, it’s of the utmost importance to act, both as prevention and as therapy’s support, on the diet.

Particularly, it’s important to limit the consumption of simple carbohydrates, prefer whole wheat food to refined one (for example when choosing pasta, rice, flour or bread), and contrast sex hormones by eating vegetables rich in phytoestrogens (for example soybean, flaxseeds, cereals, legumes, cabbage and turnips).

It has been proved that, in about 5 months, by just modifying the diet, important metabolic results can be seen:

• Decrease of sex hormones levels.

• Increase of SHBG levels.

• Decrease of cholesterol.

• Decrease of glycemia.

• Loss of weight.

In the 40-50% of cases, this has been sufficient to bring the ovarian cycle back to normality, without use of any therapy.

A part from diet, generally it’s also recommended to do a constant and regular physical exercise, which improves the muscle insulin sensitivity; and, when necessary (typically where obesity is present), it may be of some use to administer Metformin, a drug that reduce insulin levels.

Bibliography:

-Testi:

-Immagini:

• Immagine 1
• Immagine 2
• Immagine 3
• Immagine 4

2012-02-21T19:16:14 - sara pavan

Polycystic ovary syndrome and the effects of myo-inositol in women with PCOS.

Sara Pavan

Polycystic ovary syndrome (PCOS) is a disorder of the ovaries, described for the first time by Stein and Leventhal in 1935.
Polycystic ovary syndrome is a condition in which there is a hypersecretion of androgens dependent on LH, by cells of theca interna and ovarian stroma.
The histological aspect is the arrest of follicular maturation with predominance of cells of theca, deficiency in granulosa cells and stromal hyperplasia.
PCOS produces symptoms in approximately 5% to 10% of women of reproductive age (12–45 years old).
Women are usually diagnosed in their 20s or 30s, but polycystic ovary syndrome may also affect teenage girls.
It is thought to be one of the leading causes of female subfertility and the most frequent endocrine problem in women of reproductive age.
There is strong evidence that it is a genetic disease even if the exact mechanism of hereditary transmission is not known at all.
It’s likely to appear in women with a family history of non-insulin-dependent diabetes mellitus, in women whose mothers, sisters or aunts suffer from PCOS and with premature baldness in male relatives.
The causes of PCOS are not completely understood.
It is hypothesized to be a consequence of an adrenocortical disorder, during the adrenarche that causes an excessive secretion of androgens by the zona reticularis of the adrenal gland.
Androgens are converted into estrogens which induce a hypersecretion of LH that causes an overproduction of androgens in the ovaries.
Subsequently the ovary replaces the adrenal cortex in maintaining the hypersecretion of androgens.
Aromatase, a member of the cytochrome P450 superfamily, is an enzyme responsible for the aromatization of androgens into estrogens.
It transforms androstenedione to estrone and testosterone to estradiol.
These steps include three successive hydroxylations of the 19-methyl group of androgens, followed by simultaneous elimination of the methyl group as formate and aromatization of the A-ring.
The enzyme can be found in many tissues including adipose tissue that there is in large quantities in obese women.
Obesity associated with PCOS, therefore, can worsen the condition.
Increased levels of estradiol cause a decrease in FSH production by inhibiting GnRH production in the hypothalamus and they induce a peak of LH secretion.
The decrease in serum FSH level causes atresia as they lack sufficient sensitivity to FSH to survive.
In the first phase of the menstrual cycle the levels of LH are normally lower than FSH and results in an LH / FSH ratio abnormal.
In summary the hypersecretion of androgens causes an increase in estrogen that leads to the collapse of FSH and to the peak of LH, which stimulates the production of androgens in the theca.

SYNTOMPS
• Amenorrhea or oligomenorrhea with irregular menstrual periods, which may be more or less frequent, and may range from very light to very heavy.
• Hirsutism: hair on the chin, above upper lip, on forearms, on chest, on armpits, in the perioral region of the breast, in the lower abdomen and in the pubic area.
• Acne: usually on the face. It is often severe acne, those onsets late or persistent acne that is unresponsive to treatments. It is caused by excessive release of androgens whose target organ is represented, in this case, by the hair follicle and the sebaceous gland.
• Infertility: this results directly from chronic anovulation.
Women who have this condition can get pregnant with the right surgical or medical treatments.
• Overweight / obesity: insulin resistance is often associated with PCOS and it causes a loss of use of sugars and their storage as fat.
• Recurrent miscarriage due to high presence of luteinizing hormone.

Women with polycystic ovary syndrome are more predisposed to other disorders, including insulin resistance and hyperinsulinemia, metabolic syndrome, obesity, cardiovascular problems with mixed dyslipidemia and high values of VLDL (very low density lipoprotein) and LDL (low density lipoprotein) and low values of HDL (high density lipoprotein) .
There could be a possible cancer associated with PCOS such as carcinoma and endometrial hyperplasia.

CASE STUDY
A twenty year old female, on the advice of a dermatologist, consults a gynecologist for eruption of acne, hirsutism and dysmenorrhea.
The patient is 165 cm tall, she weighs 80 kg and she has a high BMI (body mass index), element that indicates a condition of overweight.
She also declares to be a smoker and to suffer from mild hypertension.
Her aunt suffers from PCOS and her grandparents from non-insulin dependent diabetes and the gynecologist, by palpation, detects ovarian enlargement.
Laparoscopic examination may reveal a thickened, smooth, pearl-white outer surface of the ovary.

After medical history and physical examination, the doctor uses the following examinations to diagnose polycystic ovary syndrome:
1. pelvic ultrasound
2. bloods tests to estimate hormonal levels

1. Pelvic ultrasound:
Ovaries present within them several cysts, small fluid-filled cavities. They aren’t true cysts but immature follicles that remain small.
They reach the state of primordial follicles, but they don’t mature.
The follicles have a size between 2 and 8 mm and no single follicle reaches the preovulatory size (16 mm or more).
According to the Rotterdam criteria, 10 or 15 follicles should be seen in an ovary on ultrasound examination.
The follicles may be oriented in the periphery, giving the appearance of a 'string of pearls'.
The numerous follicles contribute to the increased size of the ovaries, that is, at least 6-7 times larger than normal.
2. Blood tests and hormonal dosages:
Estrogen levels : estradiol (70-220 pmol/l)and estrone
FSH levels and LH levels as tested on first days of the menstrual cycle
Androgens levels: testosterone ( < 3,5nmol/l) and testosterone free
17-ketosteroids (20-59 µmol/die)
Sex hormone binding globulin (SHBG)
DHEA and DHEAS- Dehydroepiandrosterone sulfate (1,3-6,8 µmol/l)

Others blood tests may include:
Lipid levels, LDL( <3,36 mmol/l) and HDL ( > 1,55 mmol/l)
Pregnancy test (serum HCG)
Prolactin levels (2-15 µg/l)
Thyroid function tests
Tests for glucose intolerance and insulin resistance.

The examination of the patient reports:
• high levels of testosterone and free testosterone, responsible for the lack of development of ovarian follicles, acne and hair.
• reduced levels of SHBG (sex hormone-binding protein).
• high levels of LH in the first phase of the menstrual cycle; the second or third day of period FSH levels should be higher than those of LH.
• high levels of DHEA and 17 ketosteroids.
• increase in insulin.

DIFFERENTIAL DIAGNOSIS:
The gynecologist assumes a polycystic ovary syndrome but differential diagnosis has to be made in order to exclude other diseases similar to PCOS:
• Cushing's syndrome in which we have high levels of cortisol,
• adrenocortical adenomas and carcinomas that have elevated levels of 17-ketosteroids,
• congenital adrenal hyperplasia, in which the differentiating element is represented by the presence of high baseline levels of 17 - OH - progesterone,
• adrenal or ovarian tumors androgen secreting in which the levels of testosterone are higher compared with PCOS,
• estrogen-secreting neoplasms,
• hypothyroidism,
• hyperprolactinemia.

TREATMENT:
The first suggestion could be to change lifestyle by following a diet and by physical activity.
Where PCOS is associated with overweight or obesity, weight loss is the most effective method of restoring normal ovulation/menstruation, but many women find very difficult to achieve significant weight loss.
It is important to consider each case differently because it is not the disease you have to focus on but the sick and so treatment must be weighed according to the individual.
If we consider our patient, a young woman who doesn’t want a pregnancy, the chosen treatment is the pill that regulates menstrual periods and ovulation, reduces acne, hirsutism and androgen levels.
Some patients could take a risk if they undergo a certain treatment. The oral contraceptive , in fact, may promote thrombotic formations.
In the case of our patient, smoker, hypertensive and overweight, the doctor will have to monitor the patient and opt for pills with low dosage, in order to prevent the woman from incurring new risks.
It is suggested to combine the use of pill to drugs that enhance insulin sensitivity in order to eliminate or reduce problems of acne and weight gain.

Myo-inositol and effects on women suffering from PCOS:
Several studies have reported that insulin resistance is common in PCOS women, regardless of the body mass index. The importance of insulin resistance in PCOS is also suggested by the fact that insulin-sensitizing compounds have been proposed as putative treatments to solve the hyperinsulinemia.
It is thought to be associated with a defect of the action of insulin, probably as a consequence of a deficit of D chiroinositolo, which is a component of inositol phosphoglycan, a second messenger of insulin.
The deficiency of DCI causes insulin resistance due to decreased phosphorylation of the receptor tyrosine for insulin.
A study conducted by the department of gynecology and obstetrics at the University "La Sapienza" compares the effects of a combined contraceptive pill (OCP) in combination with myo-inositol (MI) on endocrine, metabolic, and clinical parameters in patients with polycystic ovary syndrome (PCOS).
One hundred fifty-five patients with PCOS were enrolled in this prospective, open-label clinical study. Patients were assigned to receive oral treatment with OCP alone (estradiol (EE) 30 μg/gestodene 75 μg) or in combination with myo-inositol 4 g/die, for 12 months.
The results show that the combined therapy (OCP plus MI) significantly decreased hyperinsulinaemia, by positively affecting the fasting insulin and glucose levels and homeostasis model assessment-insulin resistance parameters, while no significant changes were observed in the OCP group.
Androgens serum levels decreased in both groups, but significantly more in the combined therapy group. The lipid profile was improved in the combined therapy group, by reducing low-density lipoprotein cholesterol levels and enhancing high-density lipoprotein cholesterol levels.
Inositol is a polyalcohol existing as nine different stereoisomers, two of which have been shown to be
insulin mediators: myo-inositol (MI) and D-chiro-inositol (DCI).
The D-chiro-inositol-to-myo-inositol ratio is regulated by an insulin-dependent epimerase.
We hypothesize that in the ovaries of polycystic ovary syndrome patients, epimerase activity is enhanced, leading to a local myo-inositol deficiency which in turn is responsible for the poor oocyte quality.

Myo-Inositol was once considered as a member of the vitamin B complex, however, it is not an essential nutrient, because it is produced by the human body from glucose.
It has the same molecular formula but different structure of glucose.
The D chiroinositolo has a positive effect on the regulation of ovulation and the production of androgens by increasing sensitivity to insulin.
In double-blind studies, women with PCOS who received DCI experienced the following statistically significant benefits when compared with a control group: lowered free and total testosterone, lowered blood pressure, increased insulin sensitivity and a corresponding improvement in glucose disposal, and increased frequency of ovulation.
In a direct comparison between MI and DCI only MI was able to improve oocyte and embryo quality.
The myo-inositol has many positive effects on women with PCOS:
• helps ovulation leading to an increase in mature oocytes and a decrease of immature ones,
• increases the number of oocytes collected after ovarian stimulation in patients who undergo procedures Medically Assisted Procreation,
• stabilizes the body weight of patients by improving the use of circulating glucose,
• reduces the excessive hair growth and acne decreasing levels of androgens,
• improves blood pressure and reduces cardiovascular problems related to PCOS,
• enhances lipid profile,
• improves metabolic and biochemical parameters. PCOS patients' erythrocytes undergo oxidative stress as indicated by band 3 Tyr-P values, reduced cytosolic glutathione content and increased membrane protein glutathionylation.
• has a positive effect on the prevention of GD (gestational diabetes) in women with PCOS.
Some studies have the aim to summarize and discuss available data on the myo-inositol safety both in non-clinical and clinical settings. The main outcome was that only the highest dose of myo-inositol (12 g/day) induced mild gastrointestinal side effects such as nausea, flatus and diarrhea. The severity of side effects did not increase with the dosage.
Inositol, also seems to have efficacy in the treatment of obsessive-compulsive with a positive effect on women who suffer from PCOS, a disease that may have a psychological impact.
Women whit this syndrome consider their body disfigured and this can cause problems of relationship. Besides these women have problems with pregnancy and this may lead some of them to depression.
When the patient decides to become pregnant, the Physician will have to consider the choice of others drugs that promote ovulation or a possible surgery.
http://www.ncbi.nlm.nih.gov/pubmed/21845803
http://www.ncbi.nlm.nih.gov/pubmed/22296306
http://www.nlm.nih.gov/medlineplus/polycysticovarysyndrome.html
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http://www.ncbi.nlm.nih.gov/pubmed/21417594
http://www.ncbi.nlm.nih.gov/pubmed/22223702
http://www.ncbi.nlm.nih.gov/pubmed/22223702
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Manuale di Ginecologia e Ostetricia, Pescetto, De Cecco, Pecorari, Ragni
Medicina di laboratorio, Giorgio Federici

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