Hormones in Obstetrics and Gynaecology Vijay Zutshi, Asmita Muthal Rathore, Kamla Sharma
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GYNAECOLOGY

AmenorrheaCHAPTER 1

Anjali Tempe,
Usha Raina
 
INTRODUCTION
Amenorrhea is defined as the complete absence of vaginal bleeding in a women of reproductive age, but this is a symptom and not a diagnosis.
The classification of amenorrhea into primary and secondary is of clinical value.
 
PRIMARY AMENORRHEA
Primary amenorrhea is defined as the absence of menses by 16 years of age in the presence of normal secondary sexual characteristics or by 14 years of age when there is no visible secondary sexual development.
 
IMPORTANT DIAGNOSTIC INVESTIGATIONS
 
Patient with Normal Secondary Sexual Characters
If normal secondary sexual characters are found, one should look for possibility of outflow tract obstruction – like imperforate hymen.
  • If uterus is absent on ultrasound, or the karyotyping is done. If it is 46XX. Mayer-Rokitansky-Kuster-Hauser syndrome is diagnosed. If it is 46XY, then testicular feminization syndrome is likely.
  • If ultrasound shows presence of uterus, there may be hematometra or hematocolpos.
  • If pelvic anatomy is normal, i.e., if uterus is present, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin thyroid-stimulating hormone (TSH), T3, T4 levels are performed.
  • If normal levels of gonadotropins are present, there is hypothalamic cause of amenorrhea.
  • Elevation of LH: FSH ratio shows polycystic ovaries.
  • Increased prolactin indicates prolactinoma.
  • High FSH level indicates resistant ovarian syndrome (Fig. 1.1).
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Fig. 1.1: Normal secondary sexual characters
 
PATIENTS WITH ABSENT SECONDARY SEXUAL CHARACTERS
Patient with normal height: If patient has absent secondary sexual characteristic and height is normal:
FSH/LH Estimation: If low, it indicates hypogonadotropic hypogonadism.
On Karyotyping
If it is 46XX:
  • Premature ovarian failure
  • Resistant ovary syndrome
Gonadal atresia.
If it is 46XY:
  • Enzymatic failure
  • Testicular feminization syndrome
Patient with short height and no development of secondary sexual characters.
If FSH/LH estimation is low, it indicates hypothalamic cause. If it is high, then karyotyping is needed.
45XO chromosomal pattern indicates Turner's syndrome (Fig. 1.2)
 
TREATMENT
 
Goals of Therapy
  • Treatment of cause wherever possible.
  • Estrogen replacement therapy (ERT) for hypogonadism to be combined with progestin for at least ten days in each cycle.
  • Gonadotropin therapy for hypogonadism.
  • Removal of the gonads if the karyotype is 46XY or a mosaic with 46 XY to prevent development of malignancy in the gonad.
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    Fig. 1.2: No secondary sexual characteristics
  • Plastic surgery to correct ambiguity of external genitalia and permit sexual activity.
  • Anatomic defects are dealt with surgically or nonsurgically according to situation at the appropriate time of development.
  • XY females are advised for gonadectomy as there is a 80 percent chance of malignant change developing in these gonads.
  • Primary amenorrhea patients associated with gonadal failure and hypogonadotropic hypogonadism needs cyclical estrogen and progesterone therapy to initiate, mature and maintain secondary sexual characters. Therapy is usually started with 0.625 mg per day of conjugated estrogen or 1 mg of estradiol. Estrogens can be given daily or 25 days per month and progestin (medroxyprogesterone acetate 5-10 mg) should be added 12-14 days every one to two months to prevent unopposed estrogen stimulation of the endometrium and breast. In Turner's syndrome progestins are added after the patient first experiences vaginal bleeding or after 6 months of unopposed estrogens. Alternatively, estrogen and progesterone can be given daily. Girls with gonadal dysgenesis should be monitored carefully for the development of hypertension with estrogen therapy. To promote sexual maturation, exogenous estrogen should be initiated when the patient is psychologically ready in Turner's syndrome, at approximately 12-13 years of age and after growth hormone therapy is completed.
  • If the patient is short statured, higher doses should not be used in an attempt to prevent premature closure of epiphysis.
To maximize growth, estrogen replacement therapy should be initiated in a very low dosage. For example, ethinyl estradiol, 100 ng/kg/day, or 0.3 mg conjugated estrogen every other day. The growth-promoting dosage of estrogen is much less than the amount needed to induce secondary sexual characteristics. The philosophy of treatment should be to stimulate as closely as possible the normal pubertal process by using a gradually increasing dosage of estrogen, 6which should be individualized for each patient. Beginning treatment with a very low dosage permits the attainment of maximal growth potential. The dosage should be progressively increased to induce secondary sexual development. Estrogen should be administered cyclically, for example, 21 days on, 7 days off, with medroxyprogesterone acetate (Provera), 5-10 mg per day, in the last 10 days of estrogen therapy.
  • Assessment of progress should be made with frequent OPD visits for careful documentation of growth velocity and the attainment of pubertal milestones.
  • Psychogenic support through counseling, with the goal of improving the individual's sexual self-image ′ is an essential part of the therapeutic program.
In patients with 17 alpha-hydroxylase deficiency, treatment is instituted with corticosteroid-replacement as well as estrogen and progestin.
 
FERTILITY PROSPECTS
Individuals with rare mosaic form of gonadal dysgenesis may develop normally at puberty. The decision to initiate therapy with exogenous estrogen should be based mainly on circulating FSH levels, because FSH levels in the normal range for patient's age imply the presence of functional gonads. Pregnancies can be achieved in these individuals, with success rates of over 50 percent by using donor oocytes. Occasionally, the patient with mosaicism may ovulate and conceive either spontaneously or after the initiation of ERT.
Clomiphene citrate is ineffective in inducing ovulation in patients with hypogonadism who desire pregnancy because such patients are hypoestrogenic. Ovulation induction in patients with hypogonadism with human menopausal gonadotropin (hMG) is more successful and pulsatile treatment with gonadotropin-releasing hormone (GnRH) may be used in patients who have normal pituitary function.
 
SECONDARY AMENORRHEA
Secondary amenorrhea is defined as absence of menstruation for three normal menstrual cycles or 6 months.
Causes may be physiologica l —pregnancy, lactation, and menopause. Pathological causes may be further subdivided into general causes, hypothalamic, causes, endocrine causes and local physical causes.
 
Diagnosis
A pregnancy test (urine or serum human chorionic gonadotropin) should be performed in a reproductive age woman (with normal secondary sexual characteristics) and a normal pelvic examination.
  • Assessment of estrogen status: Traditionally estrogen status has been determined by giving medroxyprogesterone acetate either 5 mg or 10 mg for ten days to determine whether a patient bleeds after withdrawal of the medication (usually 2-10 days after the last dose). If there is no withdrawal bleeding in a patient with secondary amenorrhea and an apparently normal estrogen status, a progesterone challenge will diagnose Asherman's syndrome. About 2.5 mg conjugated estrogen or 2 mg-micronised estradiol can be given for 25 days with 5-10 mg of medroxyprogesterone acetate added for the last 10 days. If no bleeding occurs with this regime in a patient with secondary amennorhea and no physical abnormalities, Asherman's syndrome is diagnosed.
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    Fig. 1.3: Progesterone challenge test
  • TSH levels: Sensitive TSH assays can now be used to evaluate hypothyroidism and hyperthyroidism. Further evaluation for thyroid disorder is required if abnormalities in TSH are found.
  • Hyperprolactinemia is a common cause of anovulation in women. If elevated TSH and prolactin levels are found, the hypothyroidism should be treated before hyperprolactinemia is treated. Often the prolactin level will normalize with treatment of hypothyroidism because thyroid-releasing hormone, which is elevated in hypothyroidism, stimulates prolactin secretion.
  • FSH levels: Serum FSH levels are required to determine whether the patient has hyper-gonadotropic, hypogonadotropic or eugonadotropic amenorrhea. A circulating FSH level 8of > 40 mIU/ml indicated on at least two occasions is indicative of hypergonadotropic amenorrhea. Hypergonadotropism signifies that the cause of amenorrhea is at the level of ovary. The history should determine whether chemotherapy or radiotherapy are the cause for ovarian failure.
  • Tubercular endometritis is ruled out by family history or past history of tuberculosis. The diagnosis is often accidentally made following diagnostic curettage or at laparotomy or laparoscopy.
The underlying disorder should be treated whenever possible. Patients with unsuspected pregnancy may be counseled regarding the options for continued care.
 
TREATMENT OF SECONDARY AMENORRHEA
The underlying disorder should be treated whenever possible. Patients with unsuspected pregnancy may be counseled regarding the options for continued care. When thyroid abnormalities are discovered, thyroid hormone, radioactive iodine, or antithyroid drugs may be administered as appropriate.
  • Hyperprolactinemia is treated with Bromocryptine. Rarely, surgery is needed for large pituitary tumors.
  • It may be necessary to treat individuals with pan hypopitutarism with various replacement regimens once all the deficits have been elucidated.
These regimens include estrogen replacement for lack of gonadotropins, corticosteroid replacement for lack of ACTH, thyroid hormone for lack of TSH and DDAVP (1-deamino-8-D-AVP) to replace vasopressin.
Chronic anovulation PCO syndrome may be treated after identifying the desires of the patients. Patients often are concerned about their lack of menstruation but do not have accompanying hirsutism or infertility. The endometrium of these individuals should be protected from environment of unopposed estrogen that accompanies the anovulatory state. This is most often done with the cyclic administration of medroxyprogesterone acetate to induce withdrawal bleeding. A 10 mg daily dose for 10 days per month (or every other month) should induce withdrawal bleeding and protect the endometrium from hyperplastic transformation. This treatment option, however, is not sufficient to cause withdrawal bleeding in patients who are hypoestrogenic (i.e., anorexia nervosa). In these individuals, estrogen replacement must be added to the progestin regimen for successful menstrual regulation. Occasionally, ovulation may be associated with cyclic progestin administration.
When chronic anovulation is caused by attenuated congenital adrenal hyperplasia, corticosteroid administration (i.e., dexamethasone 0.5 mg at bedtime) is sometimes successful in restoring the normal feedback mechanism, thereby permitting regular menstruation and ovulation. A large number of patients with amennorrhea and chronic anovulation seek care because they are unable to conceive. Ovulation induction is generally the treatment of choice for such patients. Clomiphene citrate is the usual first choice for ovulation induction in these patients. Most commonly recommended dose is 50 mg daily for 5 days. Doses higher than 50 mg per day for five days are usually ineffective and patients need changes in therapy. Longer courses of clomiphene citrate therapy as well as adjunctible therapy with glucocorticoids and hCG have been recommended.
Women who fail to ovulate with clomiphene citrate as well as women with hypogonadotropic hypoestrogenic anovulation may be candidates for therapy with hMG. Administrative protocol 9and dosages vary widely and should be adjusted to individual needs. Safe administration require careful monitoring of ovarian response with ultrasonography and sexual estradiol measurements. In general, hMG is administered at a dose of 75-150 IG/day by intramuscular injection for 2-4 days, after which estradiol and follicular monitoring commence. In most cycles, gonadotropin administration lasts from 7-12 days, ovulation is triggered by i/m injection of 5,000 – 10,000 U hCG once the lead follicle reaches 16-20 mm in diameter on ultrasound assessments. Ovulation generally occurs approximately 36 hours after hCG administration. Luteal phase support is sometimes given with additional injections of hCG or with progesterone supplementation.
Ovulation induction with GnRH may be effective in patients with chronic anovulation associated with low levels of estrogen and gonadotropins. In order for therapy to be successful, a functional ovary and pituitary gland must be present.
 
CONCLUSION
Examination of patient with amenorrhoea should begin with detailed history and physical examination.
  • Primary amenorrhoea with normal secondary characteristics is commonly due to anatomical defects and surgical treatment is required for coital functions. Cryptomenorrhea can be completely cured by surgical treatment.
  • Hypoplastic secondary characteristics in patients of primary amenorrhea may be due to hypothalmopituitary or ovarian etiology.
  • Turner's syndrome is the most common type of dysgenetic gonad.
  • Amenorrhea with heterosexual characteristics are due to adult onset congenital adrenal hyperplasia or XY female.
  • Secondary Amenorrhea:
    Laboratory tests include pregnancy test, S. T3,T4 and TSH testing, S. prolactin.
    —If history, physical examination and TSH and prolactin levels are normal, a patient with normal withdrawal bleeding after progestin challenge test can be diagnosed as having anovulatory amenorrhea.
    —If there is no withdrawal bleeding after progestin challenge, those women have inadequate endometrial function.
  • Secondary amenorrhoea due to PCOD and hyper prolactinemia have good prognosis.
  • Chances of fertility are poor in genital tuberculosis, although infection can be cured.
  • Psychological support to patient wherever applicable.
 
KEY POINTS
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REFERENCES
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  1. McClamrock HD, Adashi EY. Ovulation induction. Appropriate use of clomiphene citrate. The female patient; 13:92–106, 1988.
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