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The hormone domino effect

Polycystic Ovarian Syndrome (PCOS) (Also called Stein-leventhal Syndrome) is now estimated to affect up to 20 per cent (1 in 5) of women of reproductive age worldwide, making it one of if not the most common hormonal (endocrine) disorders among women in this age group.  Three-quarters of women with PCOS struggle with fertility. Researchers agree that PCOS is responsible for the majority (perhaps 90 per cent) of adult female acne and is a culprit in excessive facial/body hair (Hirsutism), scalp hair loss and obesity.  It may also account for as many as 50 per cent of all female hormone-linked cases of infertility. Despite these astounding figures, most women who have PCOS are completely unaware they have this condition.

Although PCOS was first recognised in 1930, it is only in the past 10 years that there has been research into its cause and only in the past 2 to 3 years that practitioners have started to become aware of this research and so are starting to recognise the syndrome in their patients.   In this condition, there are multiple follicular cysts on the ovaries, which may show as enlarged and have a peripheral ‘necklace’ pattern of relatively uniformly sized, small follicles when diagnosed via ultrasound or during laparoscopy.

Multiple follicles start to grow, and, in the more severe conditions, none ripen sufficiently to release an egg. There is often, therefore, irregularity or an inability to ovulate. This can be confirmed through temperature readings or blood tests to show progesterone levels. Thirty-five per cent of female infertility, and 40 per cent of amenorrhoea (absence of menses), may be due to PCOS.

PCOS is the most common disorder that affects ovulation! The adrenal glands that are situated on top of the kidneys may slightly over-produce the male hormones such as testosterone, which are later converted in the body fat, to oestrogen. This in turn leads to a disturbance in the normal production of FSH and LH. LH may be excessively released in comparison to FSH, this can stimulate the ovaries to become packed full of these many tiny cysts.

The levels of LH to FSH can be greater than 2.5:1 ratio. The pituitary hormone Prolactin may also be over-produced, which may be evident by a milky secretion from around the nipples of the breasts. Very occasionally, PCOD may cause the ovaries to ‘run out of viable eggs’ much earlier than normal, thus, leading to a state of Ovarian Failure or Premature Menopause.  PCOS may start in the womb – researchers at the French national institute of health and medical research believe that excess exposure to the anti-Mullerian hormone before birth that may trigger overstimulation of brain cells that can raise the level of testosterone.  Anti-Mullerian hormone generally declines with age.

Symptoms of PCOS

About 50 to 75 per cent of women with PCOS do experience symptoms and not all are seen in every woman.

  • Excessive, dark, coarse hair growth on the face, chest, abdomen, etc.
  • Scalp hair loss (in classic ‘male baldness’ pattern)
  • Acne (may be severe in adolescence and may last into adulthood).
  • Skin tags (acrochordons) – teardrop-sized pieces of skin (typically in the armpits or neck area).
  • Darkening and thickening of the skin, mainly on the neck, groin, and underarms or in skin folds.
  • Obesity – apple shape (often sudden and unexpected weight gain), difficulty-losing weight.
  • Irregular or infrequent periods (less than eight per year), no periods, or frequent heavy periods.
  • Infertility and recurrent miscarriages.
  • Chronic fatigue.

Polycystic Ovaries

It is important to note that polycystic ovaries are not present in all women diagnosed with PCOS. Also, many women with regular menstrual periods and normal testosterone levels may have multiple ovarian cysts.

Researchers in Australia have made an interesting observation; they discovered that most women they examined with PCOS had a shorter 2nd finger on their hand compared with their 4th finger length.  This pattern is mostly observed in males; hence the researchers suggest that these women may have been exposed to too much male hormone in the womb.

It is not known what the full cause of PCOS is, but it has been suggested that the problem stems from the ovaries, which are unable to produce the hormones in the correct proportions.  It develops when the ovaries overproduce androgens (male hormones e.g. testosterone), upsetting the normal hormone messages to the pituitary gland in the brain.   It is estimated that 1 in 70 women with PCOS have a definite abnormality in the steroid hormone production of the adrenal gland that leaks excessive male sex hormone called adult-onset congenital adrenal hyperplasia (CAH).

The hormones that may be excessive are serum testosterone, and the precursor serum 17-hydroxyprogesterone.  In the normal ovary, one dominant follicle matures and releases as an egg (ovum) every month, but in a polycystic ovary, there are only immature follicles that either don’t produce eggs at all, or, if they do, may only do so inefficiently. The follicles that fail to completely release an egg then develop into cysts on the ovaries, hence the name.

PCOS – Ultrasound microscopy view

Many women with PCOS have been found to have a condition known as Insulin Resistance, in which the cells ‘resist’ the effects of insulin, so the body has to produce more insulin to compensate. It seems that these high levels of insulin then affect the ovaries, stimulating them to produce abnormal proportions of hormones, particularly testosterone, which causes the hair abnormalities and acne. High insulin levels also lead to altered fat and cholesterol usage in the body, which can ultimately cause obesity and high blood cholesterol problems. Elevated insulin levels contribute to or cause the abnormalities seen in the hypothalamic-pituitary-ovarian axis that lead to PCOS. Specifically, hyper-insulinaemia causes a number of endocrinological changes associated with PCOS. These changes may include: Increased GnRH pulse frequency; LH over FSH dominance; decreased follicular maturation; decreased sex human binding globulin (SHBG); and increased ovarian androgen (male hormone) production.

The ‘cysts’ in polycystic ovaries are not harmful, do not require surgical removal and should not lead to ovarian cancer (?). However, the hormonal imbalance in women with PCOS can make them more susceptible to certain health problems in later life.

These may include:

*    Type – II Diabetes (particularly from Insulin Resistance).

*    Cardiovascular Disease – with blood fat abnormalities such as elevated cholesterol and triglyceride levels in the blood.

*    Endometrial Cancer – the lining of the uterus (endometrium) may thicken with abnormal cells – a precancerous condition, if periods very infrequent (less than every three months at least).

Microscopic examination of PCOS has shown various pathologies:

  • Enlargement to the whole ovary
  • Thickened capsule
  • Increased number of small cysts under the capsule
  • Absence of follicles that have ovulated or are in the process of maturing
  • Thickening and increased fibrosis of the inner surface of the ovary.
  • Decreased thickness of the lining of each cyst.

There may be situations that may require surgical intervention in abnormal polycystic ovary disorders, these procedures include:

* Ovarian wedge resection;

* Laparoscopic ovarian drilling.

Possible Signs and Symptoms of PCOS

  • Excess ratio luteinising hormone (LH) to follicle stimulating hormone (FSH)
  • Increased levels of male hormones androstenedione and testosterone.
  • Elevated body mass index (BMI).

Thirty to fifty per cent of women with PCOD are calculated as overweight. The fat is also distributed in a way that more is deposited around the waist (central obesity or apple shape) waist: hip ratio. Studies of women with PCOS and suffer from increased body fat levels (BMI) have shown that even 5-10 per cent loss of body weight can help to restore a regular cycle and lead to ovulation.

Body Mass Index (BMI)

BMI = weight (kg)

Height x height (m2)

Underweight = 21, normal = 21-26, overweight = 27 and greater.

Insulin Resistant – is an abnormality of carbohydrate metabolism that increases the requirement of the secretion of insulin from the pancreas in order to metabolise blood sugars. Glucose tolerance tests (GTT) should be done to measure basal, (fasting) blood sugar, and insulin and glucose levels. Imbalances of inflammatory factors in the body is associated with insulin resistance, some of the mediators include C-reactive protein (CRP) and peptide Adiponectin. By balancing inflammation reactions in the body will in turn improve insulin utilisation and metabolic flexability.

It is estimated that 20 to 40 percent of women with PCOS have impaired insulin function; this is approximately seven times higher than women without PCOS.

Medical drugs to counter insulin resistance are: Metformin, Glucophage and Glitazones, ACTOSO, Junumet, Rosiglitazone (AvandiaO), Rezulin (Troglitazone) and Sitagliptin (Januvia). Approximately 30 per cent of patients started on Glucophage will experience gastrointestinal nausea, vomiting, abdominal bloating, flatulence, and appetite loss.  Generally, these symptoms greatly reduce or decease after several weeks of continued therapy.

The ‘Glycemic index’ of food is a reflection of how much that food raises your blood sugar. Simple carbohydrates usually have a higher glycemia index than complex carbohydrates. High glycemic foods demand a vigorous insulin response from the pancreas. Choose foods from a low-glycemic index group.

High insulin levels inhibit growth hormone (GH) production from the pituatury gland; this promotes increased fat storage / and affects control of blood cholesterol levels.  Elevated insulin also accelerates celluar turnover (speeds up ageing) and stimulates the release of cortisol from the adrenal glands, competing with DHEA. This in turn, affects sex hormone conversion leading to impaired fertility.  Insulin requires zinc, manganese and sulphur to be made.  If the body retains too much calcium to magnesium ratio will increase insulin levels.  This will antagonise the thyroid function leading to a sluggish metabolism.

Leptinis a hormone secreted by adipocytes that regulate body weight via an effect on metabolism. Leptin may play a possibly role in triggering puberty by initiating LH release once body fat levels are adequate to cope with the physiological demands of adolescence. Leptin has a role in regulation of the follicular development indirectly by control of LH and FSH secretion. This may have an important action of assisting follicular maturation and ovum development therefore affecting fertility and pregnancy. Women with increased weight gain may also show increased leptin levels and leptin resistance (poor utilisation of the hormone) that adversely affects gonadotropin release causing elevated LH levels common with PCOS, therefore contributing possible directly or indirectly to obesity and infertility. Studies have shown that supplementing the trace mineral zinc has been shown to help boost leptin regulation.

Ghrelin is a hormone that is involved with appetite regulation. Studies have found that women with PCOS have 70 per cent increased levels of ghrelin in comparison to women without PCOS. Therefore, appetite regulation may benefit women with PCOS obesity.

Lipase – the fat metabolizing digestive enzymes is vital for correct fat burning.

Obesity – the typical obesity of PCOS is described as ‘centripetal’, related to fat distribution in the centre of the body, as opposed to the thighs and hips. The, ‘apple’ opposed to ‘pear’ type of fat distribution clearly is associated with greater risk of hypertension, diabetes and lipid abnormalities. With increased numbers of fat cells or adipocytes also increases the production of inflammatory factors called cytokines (including C-reactive protein, tumour necrosis factor, and interleukin as examples).

Ketogenic dieting and Intermittent fasting helps to deplete glucose stores.  Reducing the consumption of animal products reduces IGF-1 (insulin-like growth factor-1) in the body that contributes to causing weight gain, abnormal growths and reduced longevity.  Emotionally, weight gain can be a response to feeling small in comparison to your perception of the enormity of the external world.  So internally you make yourselves larger or big.

Diabetes type II diabetes (non-insulin dependent diabetes mellitus-NIDDM):

Women with PCOS have an increased tendency toward this condition.

Medical drugs for this type of diabetes may include: ‘Starch blocker agents’ – Exenatide (Byetta, Bydureon – is a glycogen-like peptide-1 agonist injection); Precose (acarbose); Glyset (miglitol); Biguanides; Thiazolidinediones-Actos (pioglitazone), Avandia (rosiglitazone – though, may contribute to weight gain), whereas Janumet® Sitagliptin; Metformin ™ is often associated with weight loss.

Atherosclerosis – the condition of increased thickening of the arteries is suggested to be of greater risk of developing in PCOS leading to increased cardiovascular diseases. Raised cholesterol and triglycerides may also be elevated in PCOS sufferers (elevated serum, lipids and fats).

Increased Male Hormones – raised LH increases recreation of male androstenedione and subsequently increased circulating testosterone. This is worsened by the effect of raised insulin levels, which causes the liver to decrease its secretion of sex hormone-binding globulin (SHBG) that normally binds to and inactivates testosterone.

Anti-Androgen Medications: Testosterone receptor blockers may include: Aldactone (spironolactone); Cyproterone acetate; Tagamet (cimetidine). Testosterone metabolism blockers may include: Propecia (ministered), and Dutasteride.

Increased hair growth – (Hirsutism): the increase in male hormone activity stimulates the hair follicles to increase growth.

In the majority of Potential Genetic Links to PCOS: The possible candidate genes that have been investigated include those involved with the synthesis of steroid hormone, including CYPIIA (cholesterol side-chain cleavage gene) which alters androgen production; CPY19 (the gene encoding P450 aromatase) and CYP17 (17-hydroxylase-17, 20-lysase gene); insulin receptor gene (VMTR); follistatin gene, involved in gonadotropin action. All have been considered as genetic causes but to date none have been conclusively proven.

Androgenic Alopecia – (progressive, non-scarring scalp hair loss) can be diffused over crown with preservation of the frontal hairline.

Medication may include; anti-androgen drugs; weight loss to decrease circulation of male hormones. Camouflage with hair styling (wigs). Drugs – Minoxidil (Rogaine solution) topical lotion.

Acanthosis Nigricans – this is an eruption of skin, with increased keratin, papillomatosis (giving the skin a velvety appearance) and pigmentation. Usually occurs in the armpits, nape of neck and under breasts – associated with insulin resistance.

Hidradenitis suppurtiva – is other skin condition seen in PCOS that involved inflammation of the specialised sweat gland in the armpit and groin areas.

Acne – is chronic inflammation of the sweat ducts of the skin. It usually occurs during the early teenage years and in most people it disappears by the age of 21 though PCOS sufferers it may persist.

Acne can be due to the increased male hormone circulation associated with PCOS, the sebaceous glands at the base of the hair follicles increase their secretions of sebum. As the androgens become more active, further enlargement of the sebaceous glands occurs and even more sebum is produced which promotes the growth of a bacterium called Propioni-bacterium acne (P-acnes), which thrives in the sebaceous environment.

The bacterium digests the sebum, making it more viscous, as well as producing inflammatory by-products. In response to this inflammation, there is increased formation of the protein Keratin, which plugs up the follicles, resulting in the development of small cysts called comedones, which are the initial lesions of acne.

If these cysts are disrupted, they release inflammatory mediators, which result in the formation of a papule, pustule or cyst.

Acne primarily affects the face, and less often the back and chest. It may present in blackheads (these are non-inflamed lesions with a black colour due to the laying down of the pigment melanin). When closed, these are known as white heads.

The various lesions of acne often change from one type to another. They can result in scarring, which becomes significant in only a minority of people.

Medical drugs used to reduce obesity may include: Orlistat (Xenical) reduces fat absorption, and Sibutramine (Reductil) an appetite suppressant. Even a 5 per cent reduction in body fat has shown to greatly improve IVF success and the ability to achieve conception.