Amenorrhoea Flashcards
Definition of Amenorrhoea?
DEFINITION
Amenorrhea literally means absence of menstruation. It is a symptom and not a disease. Overall prevalence of pathologic amenorrhea is about 3-4%.
There are at least five basic factors involved in the onset and continuation of normal menstruation. These are (Fig. 29.1):
■Normal female chromosomal pattern (46,XX)
Coordinated hypothalamo-pituitary-ovarian (HPO) axis
■ Anatomical presence and patency of the outflow tract
■Responsive endometrium
■Active support of thyroid and adrenal glands.
What are the Clinical types of Amenorrhoea?
Cryptomenorrhoea?
Summary of Cryptomenorrhoea?
For descriptive purposes, the following types are conveniently described (Flowchart 29.1). This will help the clinicians to sort out the clinicopathological entity.
Physiological
Before Puberty
The pituitary gonadotropins are not adequate enough to stimulate the ovarian follicles for effective steroidogenesis → estrogen levels are not sufficient enough to cause bleeding from the endometrium.
During Pregnancy
Large amount of estrogens and chorionic gonadotropins secreted from the trophoblasts suppress the pituitary gonadotropins→ no maturation of the ovarian follicles.
During Lactation
High level of prolactin inhibits ovarian response to follicle-stimulating hormone (FSH) → no follicular growth → hypoestrogenic state no menstruation. If the patient does not breastfeed her baby, the menstruation returns by 6th week following delivery in about 40% and by 12th week in 80% of cases. If the patient breastfeeds her baby, the menstruation may be suspended in about 70% until the baby stops breastfeeding.
Following Menopause
No more responsive follicles are available in the ovaries for the gonadotropins to act. As a result, there is cessation of estrogen production from the ovaries with elevation of pituitary gonadotropins.
Pathological
Cryptomenorrhea
In cryptomenorrhea, there is periodic shedding of the endometrium and bleeding but the menstrual blood fails to come out from the genital tract due to obstruction in the passage.
Causes
■ Congenital
Acquired
Congenital
■Imperforate hymen
■Transverse vaginal septum
■Atresia of upper-third of vagina and cervix.
Morbid pathological changes, clinical features and treatment of the congenital etiology have been described in Chapter 4.
Acquired
■Stenosis of the cervix following amputation, deep
cauterization and conization. Secondary vaginal atresia following neglected and difficult vaginal delivery.
Pathology
There is only accumulation of blood in the uterine cavity resulting in hematometra, in neglected cases, the blood may enter the tubes whose fimbrial ends get blocked resulting in distension of the tubes by blood → hematosalpinx. May result in endometriosis (c.f. retrograde menstruation).
Clinical features
The patients with history of any of the etiological factors mentioned earlier, complain of:
■Amenorrhea dated back from the events
■Periodic pain lower abdomen.
Pelvic examination reveals the offending lesion either in the vagina or cervix. The uterus is symmetrically enlarged.
Treatment
Simple dilatation of the cervix so as to drain the collected blood is enough. In cases of secondary atresia of the vagina, reconstructive surgery is to be performed, to maintain the patency.
SUMMARY OF CRYPTOMENORRHEA
Cryptomenorrhea is a condition where the menstrual blood Fails to come out from the genital tract due to obstruction in the passage.
Causes
The most common cause is congenital due to imperforate hymen. The acquired cause is rare due to cervical stenosis following amputation, conization or deep cauterization.
Pathophysiology
If the site of obstruction is low down in the vagina, the accumulated blood results in hematocolpos→ hematometra → hematosalpinx. If the obstruction is at the cervix, it will produce hematometra → hematosalpinx, Hematocolpos produces marked elongation of the urethra → retention of urine.
Clinical features
The patient aged about 13-15 (congenital type) complains of periodic pain lower abdomen. Hematocolpos is usually associated with urinary problems to the extent of retention of urine. Abdominal examination reveals an uniform globular mass in the hypogastrium. Vulvar inspection reveals the bulging hymen. Rectal examination confirms the fullness of the vagina and uterine mass.
Management
• Cruciate incision of the hymen and drainage of blood (Fig. 4.3).
Dilatation of the cervix in stenosis.
Primary Amenorrhoea:
Definition
Etiopathogenesis
DEFINITION
A young girl who has not yet menstruated by her 16 years of age is having primary amenorrhea rather than delayed menarche. The normal upper age limit for menarche is 15 years.
In view of lower mean age of menarche, currently a cut off value at 14 years (in the absence of secondary sexual characters) and 16 years (regardless of the presence of secondary sexual characters) is being considered.
Etiopathogenesis
The causes of primary amenorrhea are grouped as follows:
Hypergonadotropic hypogonadism (43%)
Primary ovarian failure (p. 389).
Resistant ovarian syndrome (p. 389).
Galactosemia: Due to premature ovarian failure (p. 389).
• Enzyme deficiency (17-a-hydroxylase deficiency)- characterized by cortisol and↑ adrenocorticotropic hormone (ACTH), ↑ mineralocorticoids production, ↑progesterone (>3 ng/mL). There is hypertension with hypernatremia and hypokalemia. The individual may be 46,XX or 46,XY with primary amenorrhea and no secondary sexual characters.
• Others-gonadotropin receptor mutations-rarely FSH and/or LH levels are high as the respective receptor may be absent or mutated.
■ Developmental defect of genital tract (30%)
• Müllerian agenesis/dysgenesis
• Imperforate hymen (Fig. 4.3).
Transverse vaginal septum (TVS)
• Atresia upper-third of vagina and cervix (Fig. 4.6) Complete absence of vagina (Fig. 29.2)
Absence of uterus in Mayer-Rokitansky-Küster-
Hauser (MRKH) syndrome (Fig. 29.3 and Table 28.1).
■Hypogonadotropic hypogonadism (27%)
• Delayed puberty (constitutional)-delayed gonadotro- pin-releasing hormone (GnRH) pulse reactivation.
• Hypothalamic and pituitary dysfunction-gonadotropin deficiency due to stress, weight loss, excessive exercise, anorexia nervosa, chronic disease (tuberculosis).
• Kallmann’s syndrome-inadequate GnRH pulse secretion reduced FSH and luteinizing hormone (LH) (p. 390).
• Central nervous system tumors-craniopharyngioma → reduced GnRH secretion reduced FSH and LH.
■Abnormal chromosomal pattern
• Turner’s syndrome (45,X) (Figs. 28.2A and B)
Various mosaic states 45,X/46,XX
Pure gonadal dysgenesis (46,XX or 46,XY)- phenotypically female with streak gonads. Stature is average with some secondary sexual characters
• Androgen insensitivity syndrome (testicular femini- zation syndrome) 46,XY (Fig. 28.5)
• Partial deletions of the X chromosome (46,XX).
When part of one X chromosome is missing-deletion of long arm of X chromosome (Xq-) leads to streak gonads and amenorrhea but no somatic abnormalities. Deletion of short arm of X chromosome (Xp) usually leads to somatic features similar to Turner’s syndrome.
■Dysfunction of thyroid and adrenal cortex
• Adrenogenital syndrome (Figs. 28.1 and 33.1).
• Cretinism.
■Metabolic disorders
⚫ Juvenile diabetes.
■Systemic illness
• Malnutrition, anemia
• Weight loss
• Tuberculosis.
■ Unresponsive endometrium
• Congenital: Uterine synechiae (tubercular).
Primary Amenorrhoea
Investigations
INVESTIGATIONS (FLOWCHART 29.2)
The basic disorders responsible for primary amenorrhea almost always have some specific clinical manifestations. The diagnosis and management of cryptomenorrhea of congenital variety has already been described in Ch. 4. Only the true primary amenorrhea is dealt with here.
When to start investigations?
The following guidelines may be of help:
No period by 16 years of age in the presence of normal secondary sexual characters.
② No period by the age of 14 in the absence of growth or development of secondary sexual characters.
However, the formula may not be applicable in all cases. A patient may come with typical features suggestive of Turner and there is no point to defer the investigation or a patient of 14 with absence of vagina should not be told to come after 2 years for investigation. Even in primary amenorrhea, the possibility of pregnancy should be kept in mind, as pregnancy can occur even prior to menarche.
The investigation protocols can be grouped as:
History
Certain types of primary amenorrhea are of heredofamilial in nature. Delayed menarche or androgen insensitivity syndrome often runs in family, the later one is often found in multiple siblings of the same family and their maternal aunts.
Medical diseases: Genital tuberculosis or diabetes though rare, may be responsible for primary amenorrhea. Such type of amenorrhea is usually associated with hypogonadism.
Other features: Abnormal loss or gain in weight within short span of time is suggestive of some metabolic disorders.
- Clinical Examination
With few exceptions, the physical signs (height, weight, arm span) are so apparent that the clinical diagnosis of etiological factors of primary amenorrhea does not seem to be difficult.
Special Investigations:
The investigation should be restricted for corroboration of clinical diagnosis and in cases where clinical diagnosis remains disputed. The appropriate investigation protocol is tabulated in Tables 29.2 and 29.3.
Diagnosis of Primary Amenorrhoea based on Clinical Examination?
Special Investigations in a case of Primary Amenorrhoea to corroborate Clinical Diagnosis
Management of Primary Amenorrhoea?
MANAGEMENT
The scope of therapeutic success in the management of primary amenorrhea is very limited.
Development Anomalies
Complete agenesis of vagina
Vaginal reconstruction is the accepted form of treatment. The principle of vaginal reconstruction is to create an avascular space between the bladder and rectum. The patency is to be maintained by a mold and graft. The commonly used materials for graft are skin or amniotic membranes. The result are quite satisfactory so far as the coital act is concerned. The ideal time of operation is prior to or soon after marriage.
Chromosomal Abnormalities
In Turner or other types of gonadal dysgenesis, short- term use of combination of estrogen and progestogen is indicated at least for development of breasts (p. 374). The gonads of XY gonadal dysgenesis should be removed for its increased development of seminoma or dysgerminoma (p. 374).
In androgen insensitivity syndrome, the ectopic gonads are to be removed after the secondary sex characters are well-developed, because they may turn to malignancy. Substitution therapy after gonadectomy is indicated to maintain the secondary sex characters. Hormone replacement therapy (HRT) with conjugated equine estrogen (Premarin 0.625 mg daily) is adequate (p. 374).
Hypothalamo-pituitary-ovarian (HPO) Axis Defect
Patients with delayed puberty, following exclusion of other causes, should be counseled and reassured. Otherwise puberty may be induced using oral estrogen and progestin therapy when there is severe delay.
Gross defects in the form of adiposogenital dystrophy or pituitary dwarfism are not amenable to any form of therapy. In mild disorders, it is possible to induce ovulation and menstruation either by treatment with gonadotropins or with GnRH analogs. Individuals with isolated gonadotropin deficiency (Kallmann’s syndrome) can be treated for induction of menstruation or ovulation. Pulsatile administration of GnRH is used for induction of ovulation. Estrogen and progestin therapy is given for menstruation.
Hypothalamic-pituitary tumors (craniopharyngioma, prolactinoma) may need therapy, surgical excision or radiotherapy. Team approach involving a gynecologist, an endocrinologist, a neurosurgeon, and a radiotherapist is ideal.
Thyroid and Adrenal Dysfunction
Gross thyroid hypoplasia (cretinism) does not respond to thyroid replacement therapy. However, mild hypothy- roidism may have good result with replacement therapy. Adrenogenital syndrome with enlarged clitoris should be treated by surgical removal of clitoris (clitoroplasty) as early as possible to avoid psychological problems. Corticosteroid therapy should be continued for a prolonged period.
Corticosteroid replacement therapy is given for 17-a-hydroxylase deficiency state.
Prolactinomas need to be treated with dopamine agonists (p. 391).
Metabolic and Nutritional
Diabetes and tuberculosis are to be treated by antidia- betic and antitubercular drug respectively. Correction of anemia and improvement of nutrition status may resume menstruation. Correction of malabsorption, weight loss, stress, and chronic diseases are to be done when indicated.
Unresponsive Endometrium
Uterine synechiae of tubercular origin should be treated by antitubercular drugs supplemented by adhesiolysis and intrauterine contraceptive device (IUCD) insertion. Hysteroscopic (p. 520) release of adhesions using scissors or electrocautery can be done. To prevent recurrence of adhesion formation, high dose estrogen and progestin therapy is given monthly for withdrawal bleeding. There is no known treatment as yet for congenital unresponsive endometrium (receptor defect).
Important points r/t Primary Amenorrhoea
POINTS
Amenorrhea is physiological before puberty, during pregnancy and lactation and following menopause Most common cause of amenorrhea in a woman of reproductive age is pregnancy.
Regular menstruation indicates cyclical ovarian function in response to intact hypothalamo-pituitary-ovarian (HPO) axis. On the other hand amenorrhea and oligomenorrhea indicates ovarian, endometrial and/or hypothalamo-pituitary-ovarian (HPO) axis dysfunction The most common cause of secondary amenorrhea (pathological) is hypothalamic dysfunction.
Most common cause of cryptomenorrhea is Imperforate hen. The symptoms include periodic lower abdominal pain and hymen occasional retention of urine. The treatment is cruciate incision of the hymen and drainage of blood.
More common causes of primary amenorrhea are gonadal failure, abnormal chromosomal pattern, developmental defect of
genital tract and disturbed function of the hypothalamo-pituitary-ovarian axis. As such detailed history, clinical examination and specific investigations most often clinch the diagnosis of primary amenonhea
(Tables 29.1 and 29.21
hypogonadotropic hypogonadism, should have CT scan to rule out CNS lesion.
Women with primary amenorrhea due to Karyotyping is not needed.
Individuals with gonadal dysgenesis and X chromosomal abnormality are less than 150 cm in height. The scope of therapeutic success in the management of primary amenorrhea is very limited
XY gonads should be removed for its increased risk of malignancy. Substitution estrogen therapy should be prescribed for the
development and maintenance of secondary sex characters. Amenorrheic patients may belong to any
of the four groups: (a) Hypergonadotropic hypogonadism; (b) Hypogonadotropic hypogonadism (c) Hyperprolactinemia; or (d) Normogonadotropic anovulation
Hypothalamic hypogonadism is associated with reduced FSH and LH. There is no follicular growth and estradiol production.
Other common causes of primary amemorrhea are: (a) Hypergonadotropic hypogonadism; (b) Chromosomal abnormality: (Developmental defect of Müllerian system (MRKH syndrome); (d) Hypogonadotropic hypogonadism; (e) Dysfunction of thyroid
and adrenal gland; (f) Systemic illness, malnutrition and juvenile diabetes.
Women with Müllerian abnormalities have associated renal abnormalities in about one-third of cases.
Conditions where breast development is absent and uterus & present (estrogen deficient state): (6) Gonadal failure (45, XO, dysgenesis), 17a hydroxylase deficiency; (b) Hypothalamic failure Neurotransmitter defect, Kallmann syndrome,
craniophanyngioma; (c) Pituitary failure: isolated gonadotropin deficiency (thalassemia major). Conditions where breast development present but uterus absent: Testicular feminization
Conditions where breast development absent and uterus absent: 17a hydroxylase deficiency with 46,XY karyotype (male). These
Individuals have Hypernatremia, hypokalemia, decreased cortisol, elevated ACTH, raised mineralocorticoid levels, hypertension, raised serum progesterone >3 ng/mL. Treatment: Cortisol administration in addition to sex steroids.
Secondary Amenorrhoea
Definition
Common Causes
Etiopathogenesis of Secondary Amenorrhoea
DEFINITION
It is the absence of menstruation for 6 months or more in a woman in whom normal menstruation has been established.
The physiological causes and cryptomenorrhea has been described earlier in this chapter. Only the true secondary amenorrhea will be discussed here.
TABLE 29.5: Common causes of secondary amenorrhea.
Hypothalamus
■Stress
■ Postpill
■Weight: Either too much loss or too much gain
■Drugs: Psychotropic and antihypertensive drugs
*Pituitary Causes:
1) Adenoma
2) Sheehan’s
- Ovary:
1) PCOS
2) POF - Uterine:
1) Synechiae (Spontaneous or Induced)
*Systemic:
1) Malnutrition
2) Hypothyroid State
3) Diabetes
Clinical features and Diagnosis of Secondary Amenorrhoea
Uterine Factors?
UTERINE FACTORS
TUBERCULAR ENDOMETRITIS
The family history or past history of tuberculosis in the patient herself may or may not be present. Physical and pelvic examination may not be informative. The diagnosis is often accidentally made following diagnostic curettage or at laparotomy or laparoscopy.
UTERINE SYNECHIAE (SYN: ASHERMAN’S SYNDROME)
There is formation of adhesions following post- abortal and puerperal curettage and also following diagnostic curettage in dysfunctional uterine bleeding. Rarely, it follows tubercular endometritis. Menstrual abnormalities include hypomenorrhea, oligomenorrhea or amenorrhea. Progesterone challenge test is negative. Hysterosalpingography shows honeycomb appearance (Fig. 38.76). Transvaginal sonography or saline infusion sonography is helpful to the diagnosis. But definitive diagnosis is made by hysteroscopy. Hysteroscopy reveals the extent of adhesions directly. It has got its therapeutic value also (p. 521).
Secondary Amenorrhoea due to Ovarian Factors?
Cause1:
Polycystic Ovarian Syndrome (PCOS):
Etiology
Pathology
Histology
Clinical features
Investigations
POLYCYSTIC OVARIAN SYNDROME (PCOS)
Polycystic ovarian syndrome was originally described in 1935 by Stein and Leventhal as a syndrome manifested by amenorrhea, hirsutism, and obesity associated with enlarged polycystic ovaries.
It is the most common endocrine disorder in a woman of reproductive age.
Etiology
This heterogeneous disorder is characterized by excessive androgen production by the ovaries mainly. PCOS is a multifactorial and polygenic condition. Dysregulation of the CYP 11a gene, upregulation of enzymes in androgen biosynthetic pathology have been suggested. Insulin receptor gene on chromosome 19p13.2 are also involved.
Diagnosis is based upon the presence of any two of the fol- lowing three criteria [American Society for Reproductive Medicine (ASRM)/European Society of Human Reproduction and Embryology (ESHRE), 2018].
Oligo and/or anovulation.
Hyperandrogenism (clinical and/or biochemical).
Polycystic ovaries.
Other etiologies [congenital adrenal hyperpla- sia (CAH)], thyroid dysfunction, hyperprolactinemia, Cushing syndrome) are to be excluded. The incidence varies between 0.5-4%, more common amongst infertile women. It is prevalent in young reproductive age group (20-30%). Polycystic ovary may be seen in about 20% of normal women. Hyperandrogenism is considered the key feature for the syndrome. Not all women with isolated polycystic appearing ovary (PAO) have PCOS. With other insults of genetic, environmental (weight gain and psy- chological stress), may develop PCOS.
Pathology
Typically, the ovaries are enlarged. Ovarian volume is increased 210 cm³. Stroma is increased. The capsule is thickened and pearly white in color. Presence of multiple (212) follicular cysts measuring about 2-9 mm in diameter are crowded around the cortex (Fig. 29.4).
Histology
There is thickening of tunica albuginea. The cysts are the follicles at varying stages of maturation and atresia. There is theca cell hypertrophy (stromal hyperthecosis). Patient may present with features of diabetes mellitus (insulin resistance).
Clinical Features
The patient complains of increasing obesity (abdomi- nal-50%), menstrual abnormalities (70%) in the form of oligomenorrhea, amenorrhea or dysfunctional uterine bleeding (DUB) and infertility. Presence of hirsutism and acne (Fig. 29.5) are the important features (70%). Virilism is rare.
Acanthosis nigricans is characterized by specific skin changes due to insulin resistance. The skin is thickened and pigmented (gray brown). Commonly affected sites are nape of the neck, inner thighs, groin and axilla (Fig. 29.6).
HAIR-AN syndrome in patients with PCOS is char- acterized by hyperandrogenism, insulin resistance and acanthosis nigricans.
Internal examination reveals bilateral enlarged cystic ovaries which may not be revealed due to obesity.
PCOS: Investigations?
Investigations
■ Sonography: Transvaginal sonography (8 MHz) is espe- cially useful in obese patient (BMI ≥ 25/23). Ovaries are enlarged in volume (≥10 cm³). Increased number (220) of peripherally arranged follicles per ovary (2-9 mm) are seen (Fig. 29.7).
■Serum values:
⚫ LH level is elevated and/or the ratio LH: FSH is >3:1. Raised level of estradiol and estrone-the estrone level is markedly elevated.
⚫ SHBG level is reduced.
• Hyperandrogenism-mainly from the ovary but less from the adrenals. Androstenedione is raised (3-5 ng/mL).
⚫ Raised serum testosterone (>1.5 ng/mL), and dehy- droepiandrosterone sulfate (DHEAS) levels.
• Elevated LH or raised LH/FSH ratio is there. But it is neither specific nor diagnostic of PCOS.
• Women with hirsutim have raised levels of dihy- drotestosterone (DHT) with the presence of the enzyme 5a-reductase.
• These women have raised levels of 3a-androstene- diol glucoronide (3a-diol-G). Nonhirsute women with PCOS have raised levels of T, DHEAS or but not 3a-diol-G)
• Raised levels of prolactin in 20% due to increased pulsatility of GnRH.
More of serine phosphorylation instead of tyrosine phosphorylation is observed in the insulin receptor.
• 31% women with PCOS have impaired OGT and 7.5% diabetes.
• Genetic predisposition of PCOS is clear. There are several susceptible genes. Two major environmental insults are weight gain and psychological stress.
• Elevated insulin levels stimulate adipocyte pro- duction of adipokines. There is release of many inflammatory mediators and other factors like IL-6, TNFQ and leptin and decrease in adiponectin.
• Insulin resistance (IR): Raised fasting insulin levels >25 µIU/mL and fasting glucose/insulin ratio <4.5 suggests IR (50%). Levels of serum insulin response >300 µIU/mL at 2 hours postglucose (75 g) load, suggests severe IR.
■Laparoscopy: Bilateral polycystic ovaries are charac- teristic of PCOS (Fig. 29.4).
Investigations in a Case of PCOS
■Ultrasonography (transvaginal preferred).
■Reassessment of BMI, BP (blood pressure), waist circumference
Serum levels of FSH, LH, TSH, total testosterone, prolactin, DHEAS, 17 OHP
2 hours oral glucose tolerance test (GTT)
■ Lipid profile.
Pathophysiology of PCOS?
Pathophysiology
Exact pathophysiology of PCOS is not clearly understood. It may be discussed under the following heads (Fig. 29.8):
■Hypothalamic-pituitary compartment abnormality
2 Androgen excess and hirsutism
Anovulation
Obesity and insulin resistance
Long-term consequences.
Hypothalamic-pituitary Compartment in PCOS
■Increased pulse frequency of GnRH leads to increased pulse frequency of LH. Leptin (a peptide, secreted by fat cells and by the ovarian follicle), insulin resistance and hyperandrogenemia are responsible for this.
■GnRH is preferential to LH rather than FSH (Fig. 29.8).
■Increased pulse frequency and amplitude of LH results in tonically elevated level of LH (Fig. 29.9).
■FSH level is not increased. This is mainly due to the negative feedback effect of chronically elevated estrogen and the follicular inhibin.
Increased free estradiol due to reduced sex hormone binding globulin (SHBG) bears positive feedback relationship to LH.
■The LH: FSH ratio is increased.
Androgen Excess
Abnormal regulation of the androgen forming enzyme (P450 C17) is thought to be the main cause for excess production of androgens from the ovaries and adrenals. The principal sources of androgens are: (a) Ovary; (b) Adrenal; (c) Systemic metabolic alteration.
■ Ovary produces excess androgens due to: (a) Stimulation of theca cells by high LH; (b) P450 C17 enzyme hyperfunction; (c) Defective aromatization of androgens to estrogen; (d) Stimulation of theca cells by IGF-1 (insulin growth factor-1) (Fig. 29.10).
■Adrenals are stimulated to produce excess androgens by: (a) Stress; (b) P450 C17 enzyme hyperfunction; (c) Associated high prolactin level (20%).
■Systemic metabolic alteration
Hyperinsulinemia causes: (a) Stimulation of theca cells to produce more androgens; (b) Insulin results in more free IGF-1. By autocrine action, IGF-1 stimulates theca cells to produce more androgens; (c) Insulin inhibits hepatic synthesis of SHBG, resulting in more free level of androgens (Fig. 29.11). Features suggestive of insulin resistance are: BMI >25 kg/m², acanthosis nigricans and waist to hip ratio >0.85.
• Hyperprolactinemia: In about 20% cases, there may be mild elevation of prolactin level due to increased pulsitivity of GnRH or due to dopamine deficiency or both. The prolactin further stimulates
adrenal androgen production. Whatever may be the etiology, the endocrinologic effects of PCOS produce a vicious cycle of events as shown in the Figure 29.8.
Anovulation
Because of low FSH level, follicular growth is arrested at different phases of maturation (2-10 mm diameter). The net effect is diminished estradiol and increased inhibin production. Due to elevated LH, there is hypertrophy of theca cells and more androgens are produced either from theca cells or stroma (Fig. 29.12).
There is defective FSH induced aromatization of and- rogens to estrogens.
Follicular microenvironment is therefore more andro- genic rather than estrogenic.
Unless there is estrogenic follicular microenvironment, follicular growth, maturation, and ovulation cannot occur. There is huge number of atretic follicles that contribute to increased ovarian stroma (hyperthecosis). LH level is tonically elevated without any surge. LH surge is essential for ovulation to occur.
Obesity and Insulin Resistance
Obesity (central) is recognized as an important contribu- tory factor. Apart from excess production of androgens, obesity is also associated with reduced SHBG. It also induces insulin resistance and hyperinsulinemia which in turn increases the gonadal androgen production. PCOS is thought to have a dominant mode of inheritance as about 50% of first degree relatives have PCOS.
Etiology of insulin resistance is unknown. Mutations of the insulin receptor gene in the peripheral target tissues (muscle and adipose tissue) and reduced tyrosine autophosphorylation of the insulin receptor, is currently thought to be an important cause. Increased central body fat leads to android obesity.
Long-term Consequences (Table 29.6)
Long-term consequences in a patient suffering from PCOS includes: The excess androgens (mainly androstenedione) either from the ovaries (mainly) or adrenals are peripherally aromatized to estrone (E₁). There is concomitant diminished SHBG. Cumulative excess unbound E2 and estrone results in a tonic hyperestrogenic state (Fig. 29.13). There is endometrial hyperplasia.
Hyperinsulinemia in the pathogenesis of Pcos?
Health risks due to PCOS?
Biochemical abnormalities associated with PCOS?
Management of PCOS?
Management: Polycystic Ovarian Syndrome Management of PCOS needs individualization of the patient. It depends on her presenting symptoms, like menstrual disorder, subfertility, obesity, hirsutism or combined symptoms. Patient counseling is important.
Treatment is primarily targeted to correct the biochemical abnormalities (Table 29.7).
Weight reduction in obese patients is the first line of treatment. Body mass index (BMI) <25 improves menstrual disorders, infertility, impaired glucose intolerance (insulin resistance), hyperandrogenemia (hirsutism, acne), and obesity. Weight reduction (2-5%) improves the metabolic syndrome and reproductive function (read below). Exercise is found beneficial.
Fertility not Desired
■Management of hyperandrogenemia (p. 484)
• Combined oral contraceptive pills are effective. Progestin suppresses LH and estrogen improves SHBG, reducing free testosterone level. Newer progestins (desogestrel) are best suited (Table 30.4). COCs reduces the risks of endometrial and ovarian cancer to normal.
Hirsutism is due to anovulation, high androgen and insulin levels, decreased hepatic SHBG production and also due to genetic sensitivity of hair follicles to androgens. Correction of metabolic syndrome (Table 29.8), improves it. Antiandrogens (cyproterone acetate, spironolactone, flutamide) may be used (p. 451).
■ Metabolic syndrome (Table 29.8): Hyperinsulinemia (insulin resistance) causes hyperandrogenemia. Insulin resistance is associated with diabetes mellitus, central obesity, dyslipidemia and hypertension. Metformin, increases insulin sensitivity, decreases weight and BMI and reduces low-density lipoprotein (LDL) cholesterol, blood pressure and the risk of developing diabetes.
■ Hyperinsulinemia contributes hyperandrogenemia in women with PCOS. Hyperinsulinemia increases the risk of dyslipidemia, cardiovascular disease, and diabetes mellitus. Insulin resistance is the principal abnormality to cause metabolic syndrome (Table 29.8). Metformin (p. 201) is used as an oral insulin sensitizing agent (see below).
Endometrial hyperplasia causes abnormal uterine bleeding. Chronic anovulation, hyperestrogenemia, obe- sity, and hyperinsulinemia cause endometrial hyperplasia even endometrial cancer. Endometrial biopsy may have to be done.
Combined oral contraceptives (COCs) is the treatment of choice to prevent endometrial hyperplasia and abnormal bleeding and endometrial cancer.
Treatment for Subfertility
Chronic anovulation is the common cause of infertility. Improvement of metabolic syndrome is essential.
Ovulation induction is usually achieved by clomiphene citrate or letrozole following correction of other biochemical abnormalities (Table 29.7). In unresponsive cases, pure FSH or human menopausal gonadotropin (HMG) along with human chorionic gonadotropin (hCG) may be administered backed up with monitoring facilities (Ch. 17).
Insulin sensitizers: Women with PCOS and hyper- insulinemia with BMI >25 kg/m², ovulate satisfactorily when clomiphene is combined with metformin..
Metformin improves metabolic syndrome by reducing all the parameters: weight, BMI (hyperinsulinemia, hyper- androgenism), BP and lipid abnormalities. 500 mg thrice daily is found to correct the biochemical abnormalities. Pioglitazone and rosiglitazone are also being used in cases, resistant to metformin (Ch. 17).
Surgery (Fig. 29.14): Laparoscopic ovarian drilling (LOD) is done for cases found resistant to medical therapy (p. 500). Ovarian surface cysts are punctured up to a depth of 2-4 mm. The cysts are vaporized using monopolar cutting current (20-30 W). 4-6 punctures are made in each ovary. It has replaced the conventional wedge resection of the ovaries. Pregnancy rates following ovarian diathermy are higher. Bariatric surgery may be indicated in some PCOS women who are morbidly obese.
TABLE 29.8: Metabolic syndrome (diagnostic criteria).
- Triglyceride levels ≥150 mg/dL
- HDL-cholesterol <50 mg/dL
- Blood pressure ≥130/85 mm Hg
- Fasting glucose ≥110 mg/dL
- Waist circumference >78 cm
Presence of three abnormal findings out of the five
