Amenorrhea. A Case-Based, Clinical Guide

4. Polycystic Ovary Syndrome

Enrico Carmina 

(1)

Department of Medical and Biological Sciences, University of Palermo, Via delle Croci 47, 90139 Palermo, Italy

Enrico Carmina

Email: enricocarmina@libero.it

Abstarct

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by the pathogenetic importance of ovarian hyperandrogenism and insulin resistance and by the variable presence of four key features: (1) chronic anovulation; (2) hyperandrogenism; (3) abdominal obesity; and (4) polycystic ovaries [1].

Introduction

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by the pathogenetic importance of ovarian hyperandrogenism and insulin resistance and by the variable presence of four key features: (1) chronic anovulation; (2) hyperandrogenism; (3) abdominal obesity; and (4) polycystic ovaries [1].

Table 4.1

Phenotypes of PCOS according to Rotterdam meeting

1.Classic PCOS

(a)With polycystic ovaries

(b)With normal ovaries

2.Ovulatory PCOS

3.Normoandrogenic PCOS

 

Table 4.2

Main characteristics of PCOS phenotypes

 

Androgen levels

LH/FSH

Insulin resistance

CV risk

Type I classic PCOS

Increased

Increased

Increased

Increased

Type II classic PCOS

Increased

Mild increase

Increased

Increased

Ovulatory PCOS

Increased

Normal

Mild increase

Mild increase

Normoandrogenic PCOS

Normal

Increased

Normal

Normal?

These features were already described by Stein and Leventhal in 1935 [2] and, with the notable exception of the abdominal obesity, are the components of the newer diagnostic criteria of Rotterdam and of Androgen Excess and PCOS Society [34]. The main difference between these two diagnostic approaches is that the first includes in the syndrome also patients with no clinical or biochemical hyperandrogenism while AEPCOS criteria consider essential the presence of hyperandrogenism.

Because it is sufficient that two of the key features are present to make the diagnosis; four different phenotypes may be found with Rotterdam criteria while with AEPCOS criteria three different phenotypes are observed [5]. In Table 4.1, the four main phenotypes according to Rotterdam criteria are reported.

Independently on diagnostic criteria, PCOS is a very common disorder. Studies on the prevalence of the classic form (chronic anovulation and hyperandrogenism) have shown that in most ethnic groups about 6% of adult women are affected by the disorder [6]. Including the milder or contested phenotypes, the prevalence of PCOS is probably around 10% of all adult women [7].

Clinical and Endocrine Characteristics of Main PCOS Phenotypes

Although only few studies have evaluated the clinical and endocrine characteristics of the four main Rotterdam phenotypes [812], the available data may be so summarized (Table 4.2):

1.

Type I classic PCOS represents the most common and severe form of PCOS. These patients present as group an abdominal obesity, chronic anovulation with oligomenorrhea or amenorrhea, increased levels of LH and LH/FSH ratio, increased androgens, elevated insulin, insulin resistance, and polycystic ovaries. They represent almost 60% of all PCOS patients but in some settings may represent 80–90% of all PCOS patients.

2.

Type II classic PCOS are very similar to other classic PCOS patients but are less common (only 5–10% of the total number of PCOS patients). These patients present normal ovaries and the main endocrine difference between type I and type II classic PCOS is related to LH levels and LH/FSH ratio. Although all patients with classic PCOS have increased LH and LH/FSH ratios when compared to controls, those patients with polycystic ovaries have significantly higher LH levels (and LH/FSH ratios) than patients with normal ovaries. It suggests that LH is important or in some way related to the morphologic appearance of the ovaries.

3.

Ovulatory PCOS seems to be the mild form of classic PCOS. In fact, these patients present most endocrine characteristics of PCOS but in a milder form. In fact, patients with ovulatory PCOS have intermediate values (between classic PCOS and controls) of BMI, waist circumference, testosterone, insulin, and QUICKI. Only LH is generally normal, and it represents the main endocrine difference with the other phenotypes of PCOS. On the other hand, it is well known that in many patients with classic PCOS, it is possible to get ovulation by reducing body weight [13]. Passage from classic to ovulatory PCOS and vice versa may be possible and related to sociocultural and environmental influences [1415].

4.

Patients with normoandrogenic PCOS represent a unique group. However, also these patients have a mild testosterone excess in spite of having androgen levels in the normal range [11]. This group of subjects is mostly characterized by increased LH and LH/FSH ratio but normal body weight, waist circumference, insulin, and insulin sensitivity. Probably, they are part of PCOS spectrum but may have different pathogenetic components. In fact, hyperandrogenism is very mild and insulin resistance is generally absent. Because of it, it may be correct to keep these patients separated from other PCOS patients as previously suggested by AEPCOS Committee [4].

In conclusion, the different phenotypes of PCOS not only present similarities, but also important differences in their clinical and endocrine pattern.

Amenorrhea and PCOS: Prevalence and Clinical Significance

In the original paper of Stein and Leventhal [2], the patients presented with amenorrhea, and for many years amenorrhea has been considered prevalent in women with PCOS. In 1963, Goldzieher and Axelrod reviewing the clinical data of 1,079 patients, tabulated from 187 references, reported that amenorrhea was present in the majority (51%) of the patients with PCOS [16]. More recent studies have indicated that amenorrhea, while relatively common, is present in a minority of PCOS women, with a prevalence ranging between 10 and 20% of the patients [1718]. Probably, differences in diagnostic criteria have determined such differences in prevalence.

It is unclear that the motive of the occurrence of amenorrhea in PCOS patients. Probably, differences in estrogen production may explain these differences, but it is the opinion of the author that in some PCOS patients, amenorrhea may be linked also to psychological stress. In our experience, amenorrhea is present in 12% of classic PCOS and in 15% of patients with normoandrogenic PCOS.

Abdominal Obesity as the Main Determinant of the Severity of PCOS Phenotype

Abdominal obesity is probably the most important factor that may modify the PCOS phenotype [121920]. In fact, the main difference between the different PCOS phenotypes is related to body weight and mostly to variations in abdominal adipose tissue. While some patients with mild PCOS phenotypes are obese, and at the contrary some patients with classic PCOS have normal body weight and no increased abdominal adipose tissue, only patients with classic PCOS have a significant increase of prevalence of obesity when compared to normal population [19]. In addition, changes in body weight may modify the phenotype of PCOS moving the patient from a severe to a mild phenotype and vice versa [1213]. Above all, it suggests that obesity may modify the androgenic phenotype and transform a mild androgenic phenotype (ovulatory or maybe normoandrogenic PCOS) in classic PCOS [12].

Of course, obesity is not the only one factor able to influence the PCOS phenotype. Many patients with classic PCOS have a normal body weight [14]. Although a proportion of normal weight patients with classic PCOS have increased abdominal fat quantity, in the majority of these patients abdominal fat quantity is normal [1920]. Other factors, maybe also genetic components influencing insulin resistance and/or ovarian androgen secretion may be important. However, it is probable that the phenotypic differences in PCOS are mostly related to environmental differences. The consequence is very important. Most women with classic PCOS may reverse to a mild PCOS phenotype by changing their lifestyle. It is a message that the doctor should always give to his patients.

Adolescent PCOS: Specific Problems and Diagnosis

In adolescent girls, the diagnosis of PCOS may be particularly difficult. In fact, all main diagnostic criteria that are used in adult women may be transitory or not well defined in adolescent girls. In particular, both menstrual irregularities and altered ovarian morphology may spontaneously reverse to normal pattern in few years.

In fact, several studies have shown that 40–50% of adolescent women with oligomenorrhea, or amenorrhea will have normal ovulatory menses during their adult life. Van Hoof et al. followed a cohort of 766 girls and observed that only 51% of the 67 subjects, who presented oligomenorrhea at the age of 15, had menstrual disorders at the age of 18 [21]. Similarly, in a Swedish study, 40% of 87 adolescent girls with menstrual irregularities followed for 6 years spontaneously normalized their menstrual cycles [22]. Normalization of menstrual cycles may depend on the changes in food assumption or on the maturation of ovulatory process, but it is a common phenomenon, and we should be careful in evaluating the results of treatments in adolescent girls.

In adolescent girls, also morphologic appearance of ovaries may not be definitive. On the contrary, it has been reported that multifollicular ovary is quite common during adolescence but generally reverses to normal after some years [23]. It has to be remembered that multifollicular ovary may not be easily differentiated by the polycystic ovary, in particular when, as stated in Rotterdam guidelines, hyperplasia of the stroma is not assessed. In fact, the simple count of follicular cysts does not permit to distinguish between multifollicular and polycystic ovaries. Probably, the assessment of ovarian volume or of theca hyperplasia is needed in adolescent girls [24].

Also hyperandrogenism may be transitory [23]. However, it has been reported that hyperandrogenism is relatively constant and may represent the most important symptom of PCOS during adolescence [25]. In addition, it has been suggested that progressive hirsutism may represent an important sign of PCOS [25].

Because of it, it has been suggested to delay the diagnosis of PCOS until the end of the adolescence. Others have suggested making the diagnosis on the presence of at least four out the following five criteria: clinical hyperandrogenism, biological hyperandrogenism, hyperinsulinism, oligo/amenorrhea, and polycystic ovaries [23].

However, these criteria look too much restrictive. It is probably better to diagnose PCOS in adolescence only in patients with the most severe phenotype (Type 1 classic PCOS). Also in patients with the severe phenotype, increased ovarian size and/or theca hyperplasia is probably needed to make the diagnosis. The other PCOS phenotypes cannot be diagnosed during adolescence, and girls who present incomplete symptoms should be included in a strict follow up and the final diagnosis should be determined only after 18.

Treatment of PCOS

There is not a specific treatment of PCOS, but lifestyle changes are the only form of management that may give prolonged results on all characteristics of the ­syndrome [13].

The other treatments depend on the main symptom or on specific requests of the patients. When fertility is the main concern, clomiphene should be preferred as the first-line therapy [26]. While some authors [27] claim the metformin is as effective as clomiphene, there is a large consensus that clomiphene is more effective for ovulation induction [26]. Probably, for ovulation induction, the better alternative to clomiphene is the use of aromatase inhibitors that shows a good safety profile and efficacy at least similar to clomiphene [28].

When hirsutism is the main concern estro-progestins (E-P) or spironolactone is the choice therapy [2930]. When using E-P, the progestin component is particularly important and products having antiandrogen activity such as cyproterone acetate (where available) or drospirenone should be preferred. In selected patients, with no or insufficient response to E-P, pure antiandrogens as flutamide may be used [2930]. Because of its potential hepatotoxicity, very low doses (125–250 mg/day) of flutamide have to be utilized and liver enzymes should be carefully monitored. In fact, the elevation of liver enzymes may be found with doses of flutamide as low as 250 mg/day.

When menstrual disorders, but no fertility, are the main concern, E-P or ­metformin may be used.

Finally, long-term treatment of PCOS women requires an individualization of the therapy. It is essential to know the possible risk factors and complications of the single patient, and treatments should be chosen according to it.

Clinical Case No. 1

History. A 16-year-old girl who from menarche complains of increased facial and body hair and menstrual disorders. Her menses are characterized by oligomenorrhea with phases of amenorrhea (of 4–6 months). Her past medical history and family history are unremarkable.

Examination. She is a girl with a mild diffuse hirsutism (Ferriman–Gallwey–Lorenzo scores 9) but no other physical abnormalities. She has a normal body weight (BMI 22) and waist circumference (82 cm). She has no increased skin pigmentation or striae. The blood pressure is 110/70 mm Hg and the pulse 90 per minute.

Laboratory data. In day 5 of the cycle, the following blood hormone levels are obtained.

LH 15 mUI/ml (2–9), FSH 8 mUI/ml (3–15), LH:FSH ratio 1.9 (<2)

Testosterone 48 ng/dl (20–95), SHBG 46 nmol/ml (18–114), FAI 3.6 (<8.5), DHEAS 1 μg/ml (<0.5), 17OHP 0.9 ng/ml (0.2–1)

Insulin: 11.3 μU/ml, glucose: 74 mg/dl

Cholesterol 197 mg/dl (<200), HDL-cholesterol 63 mg/dl (35–65), LDL-cholesterol 104 mg/dl (<150), triglycerides 82 mg/dl (<160)

Ovarian sonography shows polycystic ovaries (15 microcysts with a diameter between 5 and 8 mm in each ovary) that present a normal size (mean ovarian size 6.8 cm3) and no stromal hyperplasia.

Questions

1.

The most likely diagnosis in this girl is:

·            PCOS?

·            HAIR-AN syndrome?

·            Androgen secreting tumor?

·            Idiopathic hirsutism?

·            Cushing syndrome?

2.

What is the most appropriate treatment?

(a)

Estro-progestins

(b)

Metformin

(c)

Antiandrogens

(d)

Only esthetic measures and follow-up

Answer and Comment

1.

The available data do not permit a sure diagnosis. PCOS or idiopathic hirsutism are both possible diagnoses. While HAIR-AN syndrome, androgen secreting tumor, and Cushing’s syndrome may be ruled out because of the clinical history, the physical examination, and the values of androgens, it is impossible at the moment to make a diagnosis of PCOS or of another mild androgen excess disorder. In fact, while this adolescent patient presents all diagnostic criteria according to Rotterdam or AEPCOS guidelines, androgen levels and ovarian size are normal. Because menstrual disorders and polycystic ovaries may reverse to ­normal in few years, only hirsutism should be considered a probably permanent symptom.

2.

The correct answer is d: only esthetic measures and follow up. In fact, in the absence of a diagnosis, no specific therapy should be suggested. In addition, hirsutism is mild and circulating androgens are normal. Esthetic measures should be suggested to reduce the hirsutism until the diagnosis becomes clear.

Follow-Up

In another hospital, the diagnosis of PCOS was made and treatment with E-P containing cyproterone acetate was suggested. After 6 months of treatment, the following hormone and metabolic values were obtained:

·               Fasting insulin 21 μU/ml, blood glucose 71 mg/dl

·               Cholesterol 232 mg/dl, HDL-cholesterol 53 mg/dl, LDL-cholesterol 145 mg/dl, Triglycerides 145 mg/dl

Treatment with E-P was stopped

After 4 years (at age 20), the patient was reevaluated in our department. At the moment of the study, she referred normal menses and mild hirsutism (FGL scores: 9)

The following hormone and metabolic values were obtained:

·               Serum P: 8.6 ng/ml, testosterone 42 ng/dl, SHBG 45 nmol/L, FAI 3

·               Fasting insulin 10 μU/ml, blood glucose 86 mg/dl

·               Cholesterol 197 mg/dl, HDL-cholesterol 69 mg/dl, LDL-cholesterol 123 mg/dl, Triglycerides 74 mg/dl

·               Ovarian sonography showed a few microcysts but no polycystic ovaries. Ovarian size was normal and no theca hyperplasia was observed.

Conclusions

The patient presents with hirsutism and only esthetic measures (including laser therapy) were suggested.

The clinical history indicates the difficulties in making a correct diagnosis of PCOS in adolescent girls. If a diagnosis of PCOS were made, and the patient treated with a more aggressive agent (such as metformin), then the spontaneous improvement in menses and ovarian morphology would have been attributed to that therapy. In adolescence, only patients presenting with severe symptoms (hyperandrogenism, polycystic ovaries with increased ovarian size or theca hyperplasia and irregular menses) should have a diagnosis of PCOS and a specific treatment. In all other young girls, the diagnosis should be postponed until adulthood.

It is interesting to observe that this patient developed an altered lipid pattern when treated by an estroprogestin containing cyproterone acetate. Dyslipidemia is uncommon in women taking oral contraceptives (also containing cyproterone ­acetate) but may develop in patients presenting some hidden metabolic alterations. It indicates another interesting question. Does this patient also have subclinical insulin resistance? Will she develop a PCOS if the body weight increases? It is difficult to answer to these questions, but maintenance of normal body weight should be a primary objective in adolescents (and adult women) presenting with hirsutism or menstrual disorders.

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