Review of the month

Analysing Amenorrhea - 1
Managing Amenorrhea - 2
Gestational Diabetes

Dr Ameya C Purandare

Member of the Managing Council of MOGS
Mumbai
E-mail: drameyacp@gmail.com

INTRODUCTION

Menses is a cardinal event in every woman's life. Hence, the absence of menses at the usual time every month or delay in the occurrence of the first menses both cause concern which results in a gynecological referral.

Regular and spontaneous menstruation requires
(a) An intact hypothalamic–pituitary–ovarian endocrine axis;
(b) An endometrium competent to respond to steroid hormone stimulation;
(c) An intact outflow tract from internal to external genitalia.

The human menstrual cycle is susceptible to environmental influences and stressors. Missing a single menstruation rarely reflects a significant pathology. However, prolonged or persistent absence of menses may be one of the earliest signs of neuroendocrine or anatomic abnormality.

DEFINITION & INCIDENCE

Amenorrhea is defined as the absence of menses.

Primary amenorrhea, seen in approximately 2.5% of the population, is clinically defined as the absence of menses by age 13 years in the absence of normal growth or secondary sexual development; or the absence of menses by age 15 years in the setting of normal growth and secondary sexual development.

Traditionally, evaluation was usually initiated by age 16 years if normal growth and secondary sexual characteristics were present, and at age 13 years if absent. However, because of secular trends toward earlier menarche over the past half century, the evaluation should begin at age 15 years, the age when more than 97% of girls should have experienced menarche.

Secondary amenorrhea is clinically defined as the absence of menses for more than 3 cycle intervals, or 6 consecutive months, in a previously menstruating woman. The incidence of secondary amenorrhea can be quite variable, from 3% in the general population to 100% under conditions of extreme physical or emotional stress

ETIOLOGY:

TABLE 1 : CAUSES OF PRIMARY AMENORRHEA

Hypothalamic-pituitary abnormalities
Constitutional delay of puberty
Isolated GnRH deficiency
Eating disorder
Stress/exercise
Central lesions (tumors, hypophysitis, granulomas)
Hyperprolactinemia
Gonadal abnormalities
Chromosomal abnormalities
Euchromosomal gonadal agenesis or dysgenesis
Ovarian resistance syndrome
Abnormal gonadotropin function
Autoimmune gonadal failure
Idiopathic gonadal failure
Anatomic abnormalities
Imperforate hymen
Transverse vaginal septum
Congenital absence of the cervix
Mullerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome)

TABLE 2 : CAUSES OF SECONDARY AMENORRHEA

Common

Pregnancy & lactation
Hypothalamic amenorrhea
Androgen disorders: polycystic ovarian syndrome, congenital adrenal hypreplasia
Galactorrhea-amenorrhea syndrome

Less Common

Premature ovarian failure
Asherman's syndrome
Sheehan's syndrome
Tuberculosis

Rare

Diabetes
Hyperthyroidism or hypothyroidism
Cushing's syndrome or Addison's disease
Cirrhosis
Malnutrition
Irradiation or chemotherapy
Surgery

It is important to precisely diagnose and treat amenorrhea as the implications for future fertility; risks of unopposed estrogen, including endometrial hyperplasia and neoplasia; risks of hypoestrogenism, including osteoporosis and urogenital atrophy; and impact on psychosocial development significantly affect the woman's overall health and wellbeing.

PATHOGENESIS:

Pregnancy is the most common cause of amenorrhea and must be considered in every patient presenting for evaluation of amenorrhea.

HYPOTHALAMIC DEFECTS

GnRH secreting neurons of the hypothalamus originate in the olfactory bulb and migrate along the olfactory tract into the mediobasal hypothalamus and the arcuate nucleus. Normally, the arcuate nucleus releases pulses of GnRH into the hypophyseal portal system every hour. Discharge of GnRH releases LH and (FSH) from the pituitary; LH and FSH, in turn, stimulate ovarian follicular growth and ovulation. The ovarian hormones estradiol and progesterone stimulate the development and shedding of the endometrium culminating in the withdrawal bleeding.

Anovulation and amenorrhea occur due to

Interference with GnRH transport
Defects in GnRH pulse discharge
Congenital absence of GnRH (Kallmann's syndrome).

Any of these situations leads to hypogonadotropic hypogonadism

Defects of GnRH Transport
Interference with the transport of GnRH from the hypothalamus to the pituitary may occur with pituitary stalk compression or destruction of the arcuate nucleus.
Pituitary stalk transsection from trauma, compression, radiation, tumors (craniopharyngioma, germinoma, glioma, teratomas), and infiltrative disorders (sarcoidosis, tuberculosis) may cause destruction of the hypothalamus or obstruct the transport of hypothalamic hormones to the pituitary.

Defects of GnRH Pulse Production
Reduction in the normal GnRH pulse frequency or amplitude results in little or no LH or FSH release, with the result that there is no ovarian follicular development, absence estradiol secretion,finally resulting in amenorrhea.

This is the biochemical status in normal prepubertal girls and those with constitutional delayed puberty, such as in anorexia nervosa, severe stress, extreme weight loss, or prolonged vigorous athletic exertion, and in hyperprolactinemia. Amenorrhea in such cases may also be idiopathic.

Congenital GnRH deficiency

It is called idiopathic hypogonadotropic hypogonadism when it occurs as an isolated phenomenon, and Kallmann's syndrome when it is associated with anosmia.

These patients lack GnRH secretion, and express low, prepubertal levels of serum gonadotropins. Follicular recruitment and ovulation do not occur. Although more than 60% of cases are sporadic, congenital GnRH deficiency can also be inherited in an autosomal or X-linked pattern.

More common in boys with delayed puberty, constitutional delay of puberty is an uncommon etiology of primary amenorrhea in girls. Patients demonstrate delayed adrenarche and gonadarche, but ultimately go on to have normal, although delayed, pubertal development.

Functional or hypothalamic amenorrhea

This results from abnormal hypothalamic GnRH secretion in the absence of pathologic processes. There are decreased gonadotropin pulsations, absent follicular development and ovulation, and low estradiol secretion. Serum FSH levels are usually in the normal range; the setting of high FSH:LH ratio is consistent with prepubertal patterns.

It is associated with a number of environmental stressors like eating disorders and physical or psychological stress. Weight loss, of at least 10% below ideal body weight, and excessive exercise are also associated with hypothalamic amenorrhea. The female athlete triad syndrome is characterized by amenorrhea, eating disorder, and osteopenia or osteoporosis.

PITUITARY DEFECTS

Pituitary causes of amenorrhea are rare; most are secondary to hypothalamic dysfunction. However, acquired pituitary dysfunction can ensue from previous local radiation or surgery. Excess iron deposition due to hemochromatosis or hemosiderosis may destroy gonadotropes. Congenital absence of the pituitary is a rare and lethal condition.

Sheehan's syndrome, characterized by postpartum amenorrhea, results from postpartum pituitary necrosis secondary to severe hemorrhage and hypotension.

Surgical ablation and irradiation of the pituitary as management of pituitary tumors also can cause amenorrhea.

Iron deposition in the pituitary may result in destruction of the cells that produce LH and FSH. This occurs only in patients with markedly elevated serum iron levels (ie, hemosiderosis), usually resulting from extensive red cell destruction like in Thalassemia major

Pituitary microadenomas and macroadenomas also lead to amenorrhea because of elevated prolactin levels. Isolated hyperprolactinemia in the absence of adenoma is an uncommon cause of primary amenorrhea. However, the diagnosis is strongly suggested by a history of galactorrhea. Diagnosis is readily made by evaluating a serum prolactin level. Hypothyroidism may also lead to elevated prolactin levels and thereby lead to amenorrhea.

OVARIAN AND OVULATORY DYSFUNCTION

Several gonadal disorders can cause amenorrhea. The most common cause of primary amenorrhea is gonadal dysgenesis. This group of disorders is usually associated with sex chromosomal abnormalities, resulting in streak gonads, premature depletion of ovarian follicles and oocytes, and absence of estradiol secretion.

Patients present with hypergonadotropic amenorrhea regardless of degree of pubertal development.

Primary ovarian failure is characterized by elevated gonadotropins and low estradiol (hypergonadotropic hypogonadism).

Secondary ovarian failure is usually caused by hypothalamic dysfunction and is characterized by normal or low gonadotropins and low estradiol (hypogonadotropic hypogonadism).

TABLE 3: CAUSES OF PRIMARY OVARIAN FAILURE
(Hypergonadotrophic Hypogonadism).

Gonadal dysgenesis
- Turner's syndrome (45,XO)
- Turner variants
- Pure gonadal dysgenesis (Swyer's syndrome) (46,XX and 46,XY)
Idiopathic premature ovarian failure
Steroidogenic enzyme defects
Testicular regression syndrome
True hermaphroditism
Mixed gonadal dysgenesis
Ovarian resistance syndrome (Savage's syndrome)
Autoimmune oophoritis
Postinfection (eg, mumps)
Postoophorectomy
Postirradiation
Postchemotherapy

TABLE 4: CAUSES OF HYPOESTROGENIC AMENORRHEA
(Hypogonadotropic Hypogonadism).

Hypothalamic dysfunction

Kallmann's syndrome
Tumors of hypothalamus (craniopharyngioma)
Constitutional delay of puberty
Anorexia nervosa
Severe weight loss
Severe stress
Exercise

Pituitary disorder

Sheehan's syndrome
Panhypopituitarism
Isolated gonadotropin deficiency
Hemosiderosis (primarily from thalassemia major)

Ovarian Dysgenesis

If the primitive oogonia do not migrate to the genital ridge,streak gonads develop resulting in primary amenorrhea. Two intact X chromosomes are required to maintain normal oocytes. Cytogenetic abnormalities of the X chromosome account for the majority of abnormal ovarian development and function.Fetuses with 45,X karyotype demonstrate normal oocyte number at 20–24 weeks' gestation, but there is accelerated atresia resulting in absence of oocytes at birth. Similarly, women with deletions in either the long or short arm of one X chromosome also develop either primary or secondary amenorrhea.

a)Gonadal Dysgenesis with No Y Chromatin:
Turner's syndrome (45,XO or 45,XO,XX mosaics) and 46,XX gonadal dysgenesis are the most common karyotypes. Patients with Turner's syndrome usually present with primary amenorrhea. However, some patients with mosaic abnormalities may menstruate briefly and rarely some have even conceived.

b)Gonadal Dysgenesis with Y Chromatin:
Normal female sexual differentiation does not occur in the presence of testicular secretion of antimüllerian hormone (AMH) by Sertoli cells and testosterone by Leydig cells. AMH causes regression of müllerian structures, whereas testosterone and dihydrotestosterone (DHT) promote differentiation of male internal and external genitalia, respectively. A variety of disorders can result in amenorrhea in phenotypic females possessing Y chromatin material.

Ullrich-Turner syndrome, which presents as a form of early onset vanishing testes syndrome, results from a deletion mutation in the TDF region of Y chromosome. These patients have the 46,XY genotype but do not secrete testosterone or AMH, resulting in feminization of internal and external genitalia. Patients present with primary amenorrhea and gonadal failure. The syndrome is diagnosed by DNA hybridization studies showing abnormality in the short arm of the Y chromosome.

Premature Ovarian Failure

Premature Ovarian Failure is defined as the occurrence of menopause before age 40 years of age. This is because the ovaries fail secondary to depletion of ova. It is characterized by amenorrhea, increased gonadotropin levels, and estrogen deficiency.

Steroid Enzyme Defects

Genetic females with steroid enzyme defects have normal internal female genitalia and 46,XX karyotype. However, they cannot produce estradiol and thus they fail to menstruate or have breast development.

Congenital adrenal hyperplasia describes one of fifteen known defects in the steroidogenic acute regulatory (STAR) protein, which facilitates cholesterol transport from the outer to the inner mitochondrial membrane. This enzyme catalyzes an early, rate-limiting step in tropic hormone-stimulated steroidogenesis. Patients thus present with hyponatremia, hyperkalemia, and acidosis in infancy. Both XX and XY individuals are phenotypically female. These patients can survive into adulthood given appropriate glucocorticoid and mineralocorticoid supplementation. XX patients may exhibit some secondary sexual characteristics at puberty, but present with amenorrhea and premature ovarian failure due to intraovarian accumulation of cholesterol.

Ovarian Resistance (Savage's Syndrome)

Savage syndrome is characterized with elevated LH and FSH levels, and the ovaries contain primordial germ cells. A defect in the cell receptor mechanism is the thought to be the cause.

Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is one of the most common causes of secondary amenorrhea. PCOS is the most common cause of ovulatory dysfunction in reproductive-age women.

Diagnosis is based on the presence of at least two of the following characteristics:
(a) oligo- or anovulation;
(b) clinical and/or biochemical signs of hyperandrogenism;
(c) polycystic ovaries;
(d) exclusion of other etiologies (congenital adrenal hyperplasia, androgen-secreting tumors, Cushing's syndrome).

Although the exact mechanism is unknown, it appears that insulin resistance and hyperinsulinemia play an important role. Abnormally elevated insulin levels lead to increased androgens via decreased sex hormone-binding globulin, and stimulation of ovarian insulin and insulinlike growth factor-I (IGF-I) receptors.

UTERINE ABNORMALITIES ASSOCIATED WITH AMENORRHEA

Uterine abnormality	Comments
Müllerian agenesis	Mayer-Rokitansky-Küster-Hauser syndrome Congenital absence of the uterus and the upper two-thirds of the vagina. 46,XX karyotype Normally functioning ovaries. Renal and vertebral abnormalities.
Vaginal agenesis	Failure of the vagina to develop.
Transverse Vaginal Septum	Failure of fusion of the müllerian and urogenital sinus-derived portions of the vagina.
Imperforate Hymen	If the hymen is imperorate, menstrual efflux cannot occur. An adolescent presents with complaints of primary amenorrhea and cyclic pelvic pain. It may present as back pain or difficulty with defecation or urination secondary to mass effect from vaginal distention. Inspection of the vulva may reveal a purplish-red hymenal membrane bulging outward as a result of accumulation of blood above it (hematocolpos). Blood may fill the uterus (hematometra) and spill through the fallopian tubes into the peritoneal cavity. Endometriosis and vaginal adenosis are known but not inevitable complications
Asherman's Syndrome	Amenorrhea is caused by intrauterine synechiae. These synechiae develop following a overzealous dilatation and curettage (D&C) or infected products of conception(septic or unsafe abortions). In our country we must keep in mind the important and still frequent cause of tuberculous endometritis resulting in endometrial cicitriazation.

AMENORRHEA IN WOMEN WITH 46,XY KARYOTYPE

The sexually undifferentiated male fetal testis secretes müllerian-inhibiting factor (MIF) and testosterone. MIF promotes regression of all müllerian structures: the uterine tubes, the uterus, and the upper two-thirds of the vagina. Testosterone and its active metabolite DHT are responsible for embryonic differentiation of the male internal and external genitalia.

Testicular Feminization Syndrome

In testicular feminization, all müllerian-derived structures are absent. The external genital anlagen and mesonephric ducts cannot respond to androgens because of androgen receptors isensitivity. Affected individuals are therefore phenotypic females lacking a uterus and a complete vagina. They produce some estrogen, develop breasts, and are reared as girls, and therefore present with primary amenorrhea.

Pure Gonadal Dysgenesis

If the primitive germ cells do not migrate to the genital ridge, a testis will not develop, and a streak gonad will be present. Affected individuals have normal female internal and external genitalia, as neither MIF nor androgens are secreted by the streaks. Because these individuals produce no estrogen, they will not develop breasts. They are reared as girls and present clinically with either delayed puberty or primary amenorrhea.

Anorchia

If the fetal testes regress before 7 weeks' gestation, neither MIF nor testosterone is secreted, and affected individuals will present with a clinical picture identical to that of pure gonadal dysgenesis. Individuals whose testes regress between 7 and 13 weeks' gestation present with ambiguous genitalia.

Testicular Steroid Enzyme Defects

A testis with defective enzymes will produce MIF but not testosterone. Affected individuals have female external genitalia and no müllerian structures. They will be reared as girls and present clinically with either delayed puberty or primary amenorrhea.

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.

Diagnosis of Primary Amenorrhea

Chart1 outlines the diagnostic scheme for primary amenorrhea.

Pelvic examination should be done to note the presence of a vagina and uterus and no vaginal septum or imperforate hymen that might result in the failure of appearance of menses. Because pelvic examination of an adolescent girl may be difficult, pelvic ultrasound or examination under anesthesia may be required to establish the presence of a uterus.

If no uterus is present, serum testosterone levels should be measured and karyotyping done to differentiate between müllerian agenesis and testicular feminization.

Diagnosis of Amenorrhea Not Associated with Galactorrhea-Hyperprolactinemia

These patients are evaluated according to the scheme outlined in Chart 2.

The first step is the progestin challenge, which determines whether the ovary is producing estrogen but not ovulating .hence not producing progesterone. If the endometrium has been primed with estrogen, exogenous progestin will produce menses. Give either medroxyprogesterone acetate, 10 mg orally daily for 5 days, or progesterone, 100–200 mg intramuscularly as a single dose. If vaginal bleeding follows, the ovaries are secreting estrogen. If it does not, it can be concluded that there is no estrogen or that the patient has Asherman's syndrome.

Asherman's syndrome can be ruled out by the estrogen-progesterone challenge test i.e.administration of conjugated estrogen, 2.5 mg orally daily for 25 days, plus medroxyprogesterone acetate, 10 mg orally on days 16 through 25. Patients with Asherman's syndrome do not bleed following this regimen.
Hysterosalpingography and hysteroscopy also help in diagnosing Asherman's syndrome.

In a patient who does not have Asherman's syndrome and who does not respond to the progestin challenge, ovarian dysfunction may be of hypothalamic or ovarian origin. The distinction is based on the FSH level. Primary ovarian dysfunction resulting in low estradiol secretion is associated with high serum FSH.

Diagnosis of Amenorrhea Caused by Primary Ovarian Failure

Karyotyping is indicated for all women who present with premature menopause, particularly if their amenorrhea is primary. Patients with primary amenorrhea may have a steroid enzyme defect. Autoimmune oophoritis is a reversible cause of ovarian failure that must be investigated. Table 3 lists the causes of primary ovarian failure.

Diagnosis of Amenorrhea Associated with Hypothalamic–Pituitary Dysfunction

Table 4 summarizes the differential diagnosis of hypoestrogenic amenorrhea. The category includes amenorrhea associated with athletic activity, weight loss, or stress.

Differentiation of hypothalamic from pituitary dysfunction can be achieved by giving GnRH, If there is a significant history consistent with Sheehan's syndrome, pituitary function testing is indicated in order to determine the functional capacity of the gland—particularly the integrity of the pituitary–adrenal axis.

Patients who bleed in response to the progestin challenge (ie, whose ovaries are secreting estrogen) fit into one of 4 categories:
(a) virilized, with or without ambiguous genitalia;
(b) hirsute, with polycystic ovaries, hyperthecosis, or mild maturity-onset adrenal hyperplasia;
(c) nonhirsute, with hypothalamic dysfunction; or
(d) amenorrheic secondary to systemic disease.
Clinical examination and transvaginal ultrasound may be helpful in making the diagnosis of PCOS. However, 25% of normal patients have polycystic ovaries; consequently, ultrasound cannot be the sole criterion for diagnosis.

TABLE 5: CAUSES OF EUGONADOTROPIC EUGONADISM
(Progestin-Challenge Positive).

Mild hypothalamic dysfunction

Psychological disorder
Emotional stress
Weight loss
Obesity
Exercise induced
Idiopathic

Hirsutism-virilism

PCOD
Ovarian tumor
Adrenal tumor
Cushing's syndrome
Congenital and maturity-onset adrenal hyperplasia

Systemic disease

Hypothyroidism
Hyperthyroidism
Addison's disease
Chronic renal failure

Diagnosis of Amenorrhea Associated with Galactorrhea-Hyperprolactinemia

Chart 3 outlines the diagnostic work-up of patients with galactorrhea or hyperprolactinemia.

Table 6–summarizes the differential diagnosis of galactorrhea-amenorrhea.

TABLE 6: CAUSES OF GALACTORRHEA-HYPERPROLACTINEMIA

Pituitary tumors secreting prolactin

Macroadenomas (> 10 mm)
Microadenomas (< 10 mm)

Hypothyroidism
Idiopathic hyperprolactinemia
Drug-induced hyperprolactinemia

Dopamine antagonists
- Phenothiazines
- Thioxanthenes
- Butyrophenone
- Diphenylbutylpiperidine
Catecholamine-depleting agents
False transmitters (-methyldopa)

Interruption of normal hypothalamic–pituitary relationship

Pituitary stalk section

Peripheral neural stimulation

Chest wall stimulation
Nipple stimulation
Spinal cord lesion

Central nervous system disease

Encephalitis
Craniopharyngioma
Pineal tumors
Hypothalamic tumors
Pseudotumor cerebri

Patients with primary hypothyroidism have elevated thyroid-releasing hormone (TRH) levels. TRH acts to stimulate the release of prolactin and may thereby lead to galactorrhea-amenorrhea syndrome. TSH is also elevated and as it is easier to measure ,it is the screening test for hypothyroidism.

If prolactin remains elevated or is initially higher than 50–200 ng/mL, the patient should be further studied via cone view of the sella, or computed tomography (CT) or magnetic resonance imaging (MRI) scan of the sella, to rule out pituitary micro- or macroadenoma.

A meticulous history must be taken to ascertain whether the hyperprolactinemia is caused by ingestion of drugs. Prolactin secretion is inhibited by dopamine and stimulated by serotonin and TRH. Any drug that blocks the synthesis or binding of dopamine will increase the prolactin level. Prolactin is increased by serotonin agonists and decreased by serotonin antagonists.

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. Otherwise, almost all patients with primary ovarian failure fall into the category of idiopathic premature ovarian failure and cannot be made to ovulate. 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 of the ovarian cortex, 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

Uterine abnormality	Surgical treatment
Müllerian agenesis	Treatment should be offered when the patient is contemplating sexual activity involves creation of neovagina Nonsurgical creation of a vagina using serial vaginal dilators (Franks/Ingrams) McIndoe procedure involves the creation of a cavity by dissection between the urethra and bladder anteriorly and the perineal body and rectum posteriorly. The cavity is lined by a split-thickness skin graft overlying a plastic or soft silicone mold Laparoscopic vaginoplasty (Vecchietti procedure)
Vaginal agenesis	Same as Müllerian agenesis
Transverse Vaginal Septum	If the diagnosis of a complete septum is established prior to menarche, it should be incised, creating an aperture to allow drainage. Incision of a complete septum is most easily accomplished when the upper vagina is distended and the membrane is bulging, reducing the risk of injury to adjacent structures. Surgical correction of vaginal narrowing should be performed only when the patient is contemplating initiation of sexual activity. End-to-end reanastomosis of the upper and lower vaginal mucosa, which may be accomplished with the aid of a Lucite bridge.
Imperforate Hymen	Hymenectomy involving a cruciate incision on the hymenal membrane to drain the collected menstrual blood and maintain patency of the vaginal tract
Asherman's Syndrome	Hysteroscopic adhesiolysis with post procedure estrogenic stimulation of the endometrium

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

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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ASRM: Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2004 Sep; 82 Suppl 1: S33-9
American College of Obstetricians and Gynecologists. Amenorrhea (ACOG Technical Bulletin 128). Washington, D.C.: ACOG, 1989.
Speroff L, Fritz MA. Amenorrhea. In: Clinical gynecologic endocrinology and infertility. 7th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins, 2005;401-64.
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McIver B, Romanski SA, Nippoldt TB. Evaluation and management of amenorrhea. Mayo Clin Proc 1997;72:1161-9.
Laufer MR, Floor AE, Parsons KE, Kuntz KM, Barbieri RL. Hormone testing in women with adult onset amenorrhea. Gynecol Obstet Invest 1995;40:200-3.
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Dr Ameya C Purandare

Member of the Managing Council of MOGS
Mumbai
E-mail: drameyacp@gmail.com

Diagnosis

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

Psychological disorder
Emotional stress
Weight loss
Obesity
Exercise induced
Idiopathic

Hirsutism-virilism

PCOD
Ovarian tumor
Adrenal tumor
Cushing's syndrome
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

Macroadenomas (> 10 mm)
Microadenomas (< 10 mm)

Hypothyroidism
Idiopathic hyperprolactinemia
Drug-induced hyperprolactinemia

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

Interruption of normal hypothalamic–pituitary relationship

Pituitary stalk section

Peripheral neural stimulation

Chest wall stimulation
Nipple stimulation
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 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

Uterine abnormality	Surgical treatment
Müllerian agenesis	Treatment should be offered when the patient is contemplating sexual activity involves creation of neovagina Nonsurgical creation of a vagina using serial vaginal dilators (Franks/Ingrams) McIndoe procedure involves the creation of a cavity by dissection between the urethra and bladder anteriorly and the perineal body and rectum posteriorly. The cavity is lined by a split-thickness skin graft overlying a plastic or soft silicone mold Laparoscopic vaginoplasty (Vecchietti procedure)
Vaginal agenesis	Same as Müllerian agenesis
Transverse Vaginal Septum	If the diagnosis of a complete septum is established prior to menarche, it should be incised, creating an aperture to allow drainage. Incision of a complete septum is most easily accomplished when the upper vagina is distended and the membrane is bulging, reducing the risk of injury to adjacent structures. Surgical correction of vaginal narrowing should be performed only when the patient is contemplating initiation of sexual activity. End-to-end reanastomosis of the upper and lower vaginal mucosa, which may be accomplished with the aid of a Lucite bridge.
Imperforate Hymen	Hymenectomy involving a cruciate incision on the hymenal membrane to drain the collected menstrual blood and maintain patency of the vaginal tract
Asherman's Syndrome	Hysteroscopic adhesiolysis with post procedure estrogenic stimulation of the endometrium

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

Aloi JA: Evaluation of amenorrhea. Compr Ther 1995 Oct; 21(10): 575-8
ASRM: Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2004 Sep; 82 Suppl 1: S33-9
American College of Obstetricians and Gynecologists. Amenorrhea (ACOG Technical Bulletin 128). Washington, D.C.: ACOG, 1989.
Speroff L, Fritz MA. Amenorrhea. In: Clinical gynecologic endocrinology and infertility. 7th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins, 2005;401-64.
Pletcher JR, Slap GB. Menstrual disorders. Pediatr Clin North Am 1999;46:505-18.
McIver B, Romanski SA, Nippoldt TB. Evaluation and management of amenorrhea. Mayo Clin Proc 1997;72:1161-9.
Laufer MR, Floor AE, Parsons KE, Kuntz KM, Barbieri RL. Hormone testing in women with adult onset amenorrhea. Gynecol Obstet Invest 1995;40:200-3.
Pickett CA. Diagnosis and management of pituitary tumors: recent advances. Prim Care 2003;30:765-89.
Folch M, Pigem I, Konje JC. Müllerian agenesis: etiology, diagnosis, and management. Obstet Gynecol Surv 2000;55:644-9.
American College of Obstetricians and Gynecologists. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists: number 41, December 2002. Obstet Gynecol 2002;100:1389-402.
Anasti JN. Premature ovarian failure: an update. Fertil Steril 1998;70:1-15.

Dr. Parag Biniwale

Pune
Chairperson, Young Talent Promotion Committee, FOGSI
E-mail: paragbin@hotmail.com / sauravakshay@yahoo.com

Gestational diabetes mellitus (GDM) is a common disorder affecting ~ 7% of pregnancies each year. It is on the rise in our population, the rise is attributed to our dietary pattern & lifestyle.

GDM is characterized by carbohydrate intolerance that begins or is first diagnosed during pregnancy. Some researchers are recommending universal screening of all pregnant women during pregnancy; however, the American Diabetes Association (ADA) recommends screening of only moderate- and high-risk pregnancies. Early diagnosis & management of GDM helps in reducing maternal and fetal complications. Patients with GDM are at higher risk for excessive weight gain, preeclampsia, and having cesarean delivery. Babies of mothers with GDM are at higher risk for macrosomia, birth trauma, and shoulder dystocia. After delivery, these infants have a higher risk of developing metabolic derangement (hypoglycemia, hypocalcemia, hyperbilirubinemia), respiratory distress syndrome, polycythemia. These babies are at risk of being obese and suffer from type 2 diabetes.

Screening

For many years, screening for GDM was only by taking patients' history. The first concept of biochemical screening was introduced by Mahan and O'Sullivan. They proposed using the 1-hour 50-g oral Glucose Challenge Test (GCT) for screening. Risk factors for GDM include being overweight before pregnancy (BMI > 25kg/m2), having a first-degree relative with diabetes, previous H/O GDM, previous macrosomia or large-for gestational- age baby, polycystic ovarian syndrome, age > 25 years. Multiparous women have a very high prevalence of GDM (~ 13%) as compared to primigravida. At patients' first antenatal visit, providers should assess which category patients fit best. For normal-risk patients, it is widely recommended to screen with a nonfasting, 1-hour, 50-g GCT at 24–28 weeks' gestation. Cosson et al performed an observational study comparing universal screening versus selective screening for GDM. They found that the universally screened group had more favourable outcomes. Williams et al. studied 25,118 deliveries to find out prevalence of GDM in low risk population. They found that ~ 10–11% of women who delivered would never have been screened for GDM, and they were missing 4% of women with GDM.

For higher-risk patients, screening is warranted earlier in pregnancy. Patients with symptoms of polyphagia, polyuria and polydypsia, may be diagnosed with a random blood glucose test result >_ 200 mg/dl. Screening with a fasting blood glucose test has been shown to have a sensitivity of 70–90% and a specificity of 50–75%10 and is therefore not considered an adequate screening method. It is observed that a single fasting glucose screen failed to identify 60% of women with abnormal 2-hour blood glucose levels. Metzger et al. found that a 1-hour 50-g GCT value >_ 140 mg/dl would have an ~ 80% sensitivity and a proportion of women with a positive test of 14–18%. Using a cut off value of >_ 130 mg/dl increases sensitivity to ~ 90%. A positive test requires further diagnostic testing.

Diagnosis

When diagnosing GDM, clinicians must keep in mind that patients may in fact have 1) undiagnosed type 2 diabetes, 2) mild abnormal glucose tolerance before pregnancy that worsens in pregnancy because of increased insulin resistance, 3) normal glucose tolerance before after an overnight fast of at least 8 hours but not more than 14 hours and after at least 3 days of unrestricted diet including >_150 g of carbohydrate per day. If using the 100-g OGTT, the cutoff values should be fasting < 95 mg/dl, 1- hour >_ 180 mg/dl, 2-hour >_ 155 mg/dl and 3-hour > 140 mg/dl .Two or more abnormal values must be measured for the test to be considered a positive diagnostic test. When using the 2-hour 75-g OGTT, the cutoffs are the same at 1 and 2 hours. Two or more abnormal values indicate diagnosis of GDM. However, studies have shown that mothers with only one abnormal value are at increased risk for macrosomic infants and other morbidities.

Maternal and Fetal Complications

Maternal complications. Women with GDM are more prone to develop hypertensive disorders and preeclampsia. They have moderate to high risk of nongestational diabetes in the first several years postpartum. This risk is particularly high in women with marked hyperglycemia, obesity, and a diagnosis of GDM earlier than 24 weeks gestation. They are more likely to have operative delivery; caesarean or operative vaginal delivery.

Fetal complications. Fetuses born to mothers with GDM have higher risks of developing macrosomia, hypoglycemia, hyperbilirubinemia, respiratory distress syndrome, polycythemia, hypertrophic cardiomyopathy, and hypocalcemia, and these complications have been reported with varying frequency. Macrosomia is the most common morbidity, occurring in 15–45% of infants exposed to hyperglycemia. This occurs when excess glucose is transferred to the fetus as a result of maternal hyperglycemia resulting in fetal hyperinsulinemia, which is responsible for increased growth. Other maternal factors like fetal macrosomia include obesity and high concentrations of lipids and amino acids. In subjects with preexisting diabetes, 1-hour postprandial glucose levels were more predictive of fetal Macrosomia than were fasting values. Not only are there immediate risks to the fetus, but infants exposed to maternal diabetes in utero have an increased risk of diabetes and obesity in childhood and adulthood.

Treatment

Diet and exercise. The first line of management of GDM is changes in dietary habits & exercise. Patients benefit significantly by receiving dietary counselling to plan meals & thus learn to count carbohydrates. The ADA recommends that women of normal weight in the second half of pregnancy consume 30–32 kcal/kg body wt. Carbohydrate intake should be ~ 40% of total calories and should be selected from carbohydrate foods with a low glycemic index. In overweight women, this requirement should be reduced to 25 kcal/kg. Excessive calorie restriction can be monitored by checking for fasting ketonuria, especially when there is a caloric restriction > 30%.

Insulin. For years, human insulins were the only insulin options available for the treatment of GDM. The recent advent of newer insulin analogs that mimic physiological insulin action calls for more information regarding the safety and applicability of their use in GDM. The insulin analogs lispro and aspart have proven to be more effective than regular human insulin in achieving goal glucose levels and reducing the risk of fetal macrosomia. Using analogs has the advantage of dosing 5–10 minutes before meals, versus 30–45 minutes insulin and has been found to be as effective as insulin therapy for GDM treatment. Langer et al. found that glyburide was as effective as insulin for the treatment of GDM in 404 patients, despite severity of disease when fasting plasma glucose on a glucose tolerance test was between 95 and 139 mg/dl. More than 80% of GDM patients were found to achieve the established levels of control with glyburide; 71% of patients required an average dose of 10 mg of glyburide daily. There was no significant difference in neonatal birth weight, metabolic complications, and composite outcome between the two groups. Markers for advancement to insulin include inadequate glycemic control, severe restriction of carbohydrates and calories necessary to meet glycemia goals, and a fetus that is large for gestational age. Glyburide is contraindicated in those with an allergy to sulfa. The main risk of taking glyburide, as with insulin, is hypoglycemia.

Metformin. The biguanide metformin during pregnancy has mostly been studied in the first 12 weeks of gestation for patients with polycystic ovary syndrome (PCOS). Preliminary studies have shown that in women with PCOS, metformin may be safe and may reduce risk of miscarriage and development of GDM when used for the entire pregnancy. Metformin may also have a role in therapy forGDM; a multicenter trial is underway in New Zealand to address this question.

Managing delivery A policy of induction of labour at 38 weeks of gestation in diabetic women treated with insulin was associated with a reduction in the frequency of birth weight above 4000 g and above the 90th percentile. This intervention did not appear to increase the risk of caesarean section. Neonatal morbidity was rare and similar between groups. However, only one randomized controlled trial was conducted to assess this intervention. Fifty percent of women in the expectant management group had labour induction for various obstetric indications. This decreases the power of the study to show differences between groups. Only 13 women with pregestational diabetes were included. Therefore, no conclusion can be generalised to this sub-group of women.

Postpartum follow-up. Maternal insulin requirements drop markedly in the postpartum period. Because patients with GDM have a high risk of developing type 2 diabetes, it is important to continue screening these patients. After child birth, Patients should attempt to minimize insulin resistance through exercise, maintenance of normal weight, and avoidance of drugs that induce insulin resistance. The ADA has recommended an annual fasting blood glucose test, a 6-week postpartum 75-g 2-hour OGTT, and contraception to ensure that patients will not conceive in the face of marked hyperglycemia, which could lead to increased congenital malformations. Patients who had GDM in a previous pregnancy have a 33–50% likelihood of recurrence in a subsequent pregnancy. Given the well-known sequelae of diabetes, which include macro- and microvascular disease and cardiovascular disease, it is important to recognize the risk and prevent the development of diabetes in the future in women with GDM. In the Diabetes Prevention Program, intensive lifestyle modification to promote weight loss and increase physical activity resulted in a 58% reduction in the relative risk of type 2 diabetes in adults with impaired glucose tolerance. In another study with 1,079 participants aged 25–84 years, weight loss was the dominant predictor of reduced diabetes risk. Every kilogram of weight loss resulted in a 16% reduction in risk.

Summary

GDM is associated with a number of fetal and maternal complications especially if glucose levels are uncontrolled. Diagnosing women with GDM early through screening at appropriate gestational age is crucial to avoiding unfavourable outcomes. Several drugs that are both effective and safe are being used to treat women with GDM if diet and exercise fail; these include human insulin, insulin analogs, and glyburide. Studies are underway to test the safety and efficacy of metformin in pregnancy. Women with GDM should be followed postpartum and monitored for type 2 diabetes to reduce the risks for complications of diabetes. Suitable contraceptives should be recommended to the couple so that immediate conception is avoided.