Managing Amenorrhea – 2

Dr Ameya C Purandare

Diagnosis

It is absolutely essential to determine which organ is dysfunctional and then to establish the precise cause so that specific treatment can be advised
Any patient with amenorrhea who has a uterus pregnancy should be first ruled out and serum levels of thyroid-stimulating hormone (TSH) and prolactin estimated. Galactorrhea should be identified by clinical examination.

Chart 1: Work-Up for Primary Amenorrhea

Chart 2: Work-up for secondary amenorrhea

Chart 3: Work-Up for Amenorrhea–Galactorrhea–Hyperprolactinemia.

Table 5: Causes Of Eugonadotropic Eugonadism
(Progestin-Challenge Positive).

Mild hypothalamic dysfunction

1. Psychological disorder
2. Emotional stress
3. Weight loss
4. Obesity
5. Exercise induced
6. Idiopathic

Hirsutism-virilism

1. PCOD
2. Ovarian tumor
3. Adrenal tumor
4. Cushing’s syndrome
5. Congenital and maturity-onset adrenal hyperplasia

Systemic disease

• Hypothyroidism
• Hyperthyroidism
• Addison’s disease
• Chronic renal failure

Diagnosis of Amenorrhea Associated with Galactorrhea-Hyperprolactinemia

Table 6: Causes Of Galactorrhea-Hyperprolactinemia

Pituitary tumors secreting prolactin

1. Macroadenomas (> 10 mm)
2. Microadenomas (< 10 mm)

Hypothyroidism
Idiopathic hyperprolactinemia
Drug-induced hyperprolactinemia

1. Dopamine antagonists
   1. Phenothiazines
   2. Thioxanthenes
   3. Butyrophenone
   4. Diphenylbutylpiperidine
2. Catecholamine-depleting agents
3. False transmitters (-methyldopa)

Interruption of normal hypothalamic–pituitary relationship

1. Pituitary stalk section

Peripheral neural stimulation

1. Chest wall stimulation
2. Nipple stimulation
3. Spinal cord lesion

Central nervous system disease

• Encephalitis
• Craniopharyngioma
• Pineal tumors
• Hypothalamic tumors
• Pseudotumor cerebri

Treatment

Management Of Patients Desiring Pregnancy—Ovulation Induction

a)Ovulation Induction in Patients with Primary Ovarian Failure
Patients with primary ovarian failure can be made to ovulate only under very rarely. Patients with reversible ovarian failure due to autoimmune oophoritis, can be treated with corticosteroids.In vitro IVF with oocytes donation is the only option by which they can have children.Any patient with a Y chromosome should undergo oophorectomy to prevent tumor development.

b)Ovulation Induction in Patients with Hypoestrogenic Hypothalamic Amenorrhea (Progestin-Challenge Negative)
In these patients with low estrogen levels, the pituitary does not release high quantities of LH and FSH. Injections of exogenous gonadotropins (human recombinant follicle-stimulating hormone [hrFSH] or human menopausal gonadotropin [hMG]) is usually first-line therapy. Patients showing some ovarian stimulation by clomiphene can be treated with a combination of clomiphene and hMG—the advantage being a reduction in the amount of hMG required and thus a substantial costreduction. Ovulation induction with gonadotropins must be carefully monitored with serial ultrasound and estradiol determinations to avoid hyperstimulation. If a potentially reversible cause of amenorrhea can be identified like marked weight loss, it should be corrected.

c)Ovulation Induction in Patients Who Bleed in Response to Progestin Challenge
Most of these patients respond to clomiphene citrate. The starting dose is 50 mg orally daily for 5 days. This can be increased to a maximum of 250 mg orally daily in 50-mg increments until ovulation is induced. This medication is FDA-approved for use up to 150 mg/d. Ovulation occurs 5–10 days after the last dose.
Patients with elevated androgens may not respond to clomiphene citrate may respond to combined treatment with an oral hypoglycemic agent (metformin) and clomiphene. If clomiphene therapy with or without metformin is ineffective, gonadotropin therapy may be attempted. Care must be taken in using FSH in these patients, as they are likely to become hyperstimulated.

Laparoscopic ovarian drilling (LOD) is a surgical method of ovulation induction in PCOS patients. LOD involves electrocautery or laser drilling with the goal of creating foci of laser or thermal damage in the cortex and ovarian stroma. The mechanism of action may involve destruction of androgen-producing stromal cells, a sudden drop in ovarian androgen levels, improved follicular microenvironment, or increased gonadotropin secretion. This procedure may cause postoperative pelvic adhesions, resulting in tubal compromise.

d)Ovulation Induction in Patients with Amenorrhea-Galactorrhea with Pituitary Macroadenoma
Dopamine agonist drugs such as cabergoline and bromocriptine are the first-line treatment of hyperprolactinemia of any cause, including macroadenomas. These drugs can decrease prolactin secretion and tumor size. Surgical therapy, transsphenoidal or frontal removal of the pituitary adenoma or the entire gland, may be required if tumor size or secretion are resistant to dopamine agonists; the lesion is rapidly enlarging or causing symptoms such as visual changes or headaches; or in women with giant adenomas (> 3 cm) who wish to discontinue agonist treatment for conception and the duration of pregnancy.

e)Ovulation Induction in Patients with Amenorrhea-Galactorrhea without Macroadenoma (Including Patients with Microadenomas)
These patients ovulate readily in response to dopamine agonist treatment, with dose titrated until serum prolactin is normal. Patients are maintained on the lowest dose. Once pregnancy has been achieved, the agent can be discontinued. Patients with macroadenomas may need to continue therapy throughout pregnancy to avoid further growth of the lesion.

Patients taking drugs that raise the prolactin level should discontinue them if possible, but continued use of such drugs is not a contraindication to therapy.

f)Ovulation Induction in Patients with Hypothyroidism
Amenorrheic patients with hypothyroidism respond to thyroid replacement therapy.

Management Of Patients Not Desiring Pregnancy

Patients who are hypoestrogenic must be treated with a combination of estrogen and progesterone to maintain bone density and prevent genital atrophy.
Oral contraceptives are effective replacement therapy for most women.

Combinations of 0.625–1.25 mg of conjugated estrogens orally daily on days 1 through 25 of the cycle with 5–10 mg of medroxyprogesterone acetate on days 16 through 25 are an alternative. Calcium intake should be 1–1.5 g of elemental calcium daily.

Patients who respond to the progestin challenge require progestin administration to prevent the development of endometrial hyperplasia and carcinoma.
Oral contraceptive pills may be used for regularization of the menstrual cycle.. Alternatively, medroxyprogesterone acetate, 10 mg orally daily for 10–13 days every month or every other month, is sufficient to induce withdrawal bleeding and to prevent the development of endometrial hyperplasia.

Patients with hyperprolactinemia need periodic prolactin measurements and radiographic cone views of the sella turcica to check for the development of macroadenoma.

Management Of Uterine Causes Of Amenorrhea-Surgical Treatment

Sequelae

The complications of amenorrhea can be numerous, ranging from infertility to psychosocial developmental delays with lack of normal physical sexual development.

Hypoestrogenic patients can develop severe osteoporosis and fractures. The complications associated with amenorrhea in patients who respond to progestin challenge are endometrial hyperplasia and carcinoma resulting from unopposed estrogen stimulation.

Conclusion

The overall prognosis for amenorrhea is good.
One must remember and reiterate to the patient and her relatives that it is usually not a life-threatening clinical event and with proper evaluation the precise etiology can be diagnosed and treated.
Many patients with hypothalamic amenorrhea will spontaneously recover normal menstrual cycles. Virtually all amenorrheic women who do not have premature ovarian failure can be made to ovulate with a dopamine agonist, clomiphene citrate, insulin-sensitizing agents, and gonadotropins.

References

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