Amen Or Rhea

Amenorrhea Amenorrhea remains one of the few areas of gynaecologic endocrinology that remains a challenge to the managing clinician. The majority of patient with amenorrhea have relatively simple problems that can be managed easily by the patients primary care clinician. Definition of Amenorrhea: • No menses by age 14 in the absence of growth or development of secondary sexual characteristics. • No menses by age 16 regardless of the presence of normal growth and development with appearance of secondary sexual characteristics. • In a woman who has been menstruating, the absence of periods for a length of time equivalent to a total of at least 3 of the previous cycle intervals or 6 months of amenorrhea. Let it be known, that strict adherence to these criteria can result in improper management in individual cases. There is no reason to defer the evaluation of a young girl who presents with obvious stigmata of Turner syndrome. Similarly, the 14-year-old girl with an absent vagina who is otherwise completely normal should not be told to return in 2 years. A patient deserves a considerate evaluation whenever her anxieties, or those of her parents, bring her to a clinician, finally, the possibility of pregnancy should always be considered. Basic principles of Menstrual function: The clinical demonstration of the menstrual flow to some extent confirms that the menstrual function is in a good condition. This requires an intact genital outflow tract (a patent tract that connects the endometrial cavity through the cervical canal, vaginal canal and vaginal orifice). The presence of a menstrual flow depends on the existence and development of the endometrium lining the uterine cavity. This tissue is stimulated and regulated by the proper quantity and sequence of the oestrogen and progesterone hormones. These hormones are secreted by the ovary, more specifically by the evolving follicles which following ovulation becomes corpus luteum. The development of the ovarian follicle are stimulated by the gonadotropins (i.e FSH and LH) secreted by the anterior pituitary, which is stimulated by the gonadotropin releasing hormone (GnRH) which in turn is secreted from basal hypothalamus and transferred through portal vessels to the receptive cells within the anterior pituitary.

At 6-8 weeks of gestation, the first sign of ovarian differentiation is shown by the rapid mitotic multiplication of the germ cells, reaching 6-7 million oogonia by 16-20 weeks (this represent the maximal oogonal content of the gonad), and from this point onward there will be an irretrievable decrease in the germ cell population for some 50 years later, the store of oocytes will be finally exhausted. Chromosomal anomalies can accelerate germ cell loss. Individuals with Turner syndrome (45,X) experience normal migration and mitosis of germ cells, but the oogonia do not undergo meiosis, and rapid loss of oocytes leaves the gonad without follicles by birth, and it appears as a fibrous streak. The causes of amenorrhea can be segregated into the following compartments: Compartment I: Disorders of the outflow tract or uterine target organ. Compartment II: Disorders of the ovary. Compartment III: Disorders of the anterior pituitary. Compartment IV: Disorders of central nervous system (hypothalamic) factors. Evaluation of Amenorrhea: Evaluation of the patient with amenorrhea, starts with a careful history taking and physical examination which seeks the following – evidence for psychological dysfunction or emotional stress, family history of apparent genetic anomalies, signs of nutritional deprivation (i.e. anorexia nervosa), excessive weight loss, abnormal growth and development, the presence of a normal reproductive tract, and evidence for CNS disease. Thereafter, the patient is exposed to a combined therapeutic and laboratory evaluation as depicted by the flow chart below. Because galactorrhea (nonpuerperal breast lactation) is a frequent problem with those who have amenorrhea – it is always appropriate to seek for its occurrence and since there are similarities in the evaluation of these two conditions, the workup as described below is appropriate for patients with amenorrhea, galactorrhea or both. Galactorrhea is an important clinical physical sign, whether it is spontaneous or present only with careful expression by the examiner, unilateral or bilateral, persistent or intermittent.

Galactorrhea due to hormonal secretions usually come from multiple duct openings in contrast to pathologic discharge that usually comes from a single duct. The initial step in the evaluation of galactorrhea, regardless of the menstrual history, includes the measurement of TSH, prolactin level and lateral view x-ray of the skull coned down to the sella turcica. Step 1: (initial step in the evaluation of amenorrheic patient) First exclude pregnancy by doing a pregnancy test. 1. Begin with measurement of thyroid-stimulating hormone (TSH), though only a few patient presenting with amenorrhea and/or galactorrhea will have hypothyroidism that is not clinically apparent. It is pertinent to start with the evaluation of TSH, since the treatment for hypothyroidism is very simple, with prompt return of ovulatory cycles, and cessation of breast secretions for those with galactorrhea. Elevated TSH implies that there is hypothyroidism. The longer the duration of hypothyroidism, the higher the incidence of galactorrhea and the higher the prolactin levels. Therefore, the next investigation would be serum prolactin level – it is known that with hypothyroidism, the hypothalamic content of dopamine is reduced resulting in the unopposed stimulatory effect of thyrotropin-releasing hormone (TRH) on prolactin secretion from the pituitary gland. The constant pituitary gland stimulation with TRH can result in hypertrophy or hyperplasia of the pituitary. Therefore, patients with primary hypothyroidism and hyperprolactinaemia can present with either primary or secondary amenorrhea. The next investigation in the evaluation of amenorrhea is to assess the level of endogenous oestrogen and the competence of the outflow tract. There are 3 choices of progestational agents: i. Parenteral progesterone in oil (200mg). ii. Oral micronized progesterone (300mg), usually administered at bedtime to avoid sideeffects. iii. Oral medroxyprogesterone acetate, 10mg daily for 5 days. Within 2-7 days after the conclusion of progestational medication, the patient will either bleed or not bleed. For the patient that has a withdrawal bleeding, it can be reliably assumed that she had anovulation. The presence of a functional outflow tract and a uterus lined by reactive endometrium sufficiently prepared by endogenous oestrogen is confirmed.

Therefore in the absence of galactorrhea, with normal serum prolactin and TSH levels further evaluation is unnecessary. Negative withdrawal bleeding (no bleeding following progestational challenge). - there are 2 rare situations associated with a negative withdrawal response, despite the presence of adequate levels of endogenous oestrogen. In both situations, the endometrium is decidualized, and therefore, it will not be shed following the withdrawal of exogenous progestin. o Anovulatory state due to polycystic ovary syndrome, where the endometrium is decidualized in response to high androgen levels. o Specific adrenal enzyme deficiency (17 hydroxylase deficiency), where the endometrium is decidualized by high progesterone levels associated with the enzyme deficiency. All anovulatory patients require therapeutic management, because of the short latent period in the progression from normal endometrial tissue to atypia to cancer (the critical feature is the duration of exposure to constant, unopposed oestrogen). If there is any concern, evaluation of the endometrium with aspiration curettage is necessary. Minimal therapy of anovulatory women requires the monthly administration of a progestational agent: 10mg medroxyprogesterone acetate daily for the first 10 days of each month (this provides the needed protection against the growthpromoting effects of constant oestrogen stimulation). If reliable contraception is essential, the use of low-dose oral contraceptive pills in the usual cyclic fashion is appropriate. If, at any time, an anovulatory patient fails to have withdrawal bleeding on a monthly progestin programme, this is a sign (provided she is not pregnant) that she has moved to the negative withdrawal bleed category. The progestational challenge will occasionally trigger an ovulation in an anovulatory patient. The tip-off will be a later withdrawal bleed, 14 days after the progestational challenge. Note: A positive withdrawal bleeding response to progestational medication, the absence of galactorrhea, and a normal prolactin level together effectively rule out the presence of a significant pituitary tumour. -

Otherwise a negative withdrawal response implies endorgan problem (e.g., reproductive outflow tract

obstruction or preliminary oestrogen proliferation of the endometrium has not occurred). Hyperprolactinemia should draw attention to the pituitary gland, but remember that there could be ectopic production of prolactin (though rare) in pituitary tissue in the pharynx, bronchogenic carcinoma, renal cell carcinoma, a gonadoblastoma, prolactinoma in the wall of an ovarian dermoid cyst or teratoma. Step 2 in the management of amenorrheic patient is designed to clarify this situation. Step 2: Orally active oestrogen is administered in quantity and duration certain to stimulate endometrial proliferation and withdrawal bleeding provided that a completely reactive uterus and patent outflow tract exist. Oestrogen therapy: i. conjugated oestrogen 1.25mg daily for 21 days Or 2mg oestradiol daily for 21 days, the above is to induce endometrial proliferation. The addition of orally active progestational agent terminally (medroxyprogesterone acetate 10mg daily for the last 5 days) is to achieve withdrawal bleeding. In the presence of a negative withdrawal response, it is a wise precaution to have a second course of oestrogen and if still negative, a diagnosis of a defect in the endometrium or outflow tract can be confidently made. Step 3: For those amenorrheic patient, who do not have enough endogenous oestrogen to stimulate the endometrium. It would be necessary to determine whether the dysfunction is in the ovary or hypothalamo-pituitary by assaying for serum FSH and LH. Note: Because step 2 involved administration of exogenous oestrogen, which can artificially and temporarily alter the true baseline concentrations of endogenous gonadotropins, it is necessary to delay step 3 (assay of gonadotropins) for 2 weeks after step 2. Normal adult female : Serum FSH level is 5-20IU/L, with the ovulatory midcycle peak about 2 times the baseline level. Serum LH level is 5-20IU/L, with the ovulatory midcycle about 3 times the baseline level.

Hypogonadotropic hypogonadism – (prepubertal, hypothalamic or pituitary dysfunction) Serum FSH level is less than 5IU/L and serum LH level is also less than 5IU/L, there would be a need for lateral view skull x-ray, coned down to the sella turcica to exclude pituitary hypertrophy. Hypergonadotropic hypogonadism (postmenopausal, castrate or ovarian failure): Serum FSH level will be greater than 20IU/L, just as serum LH level will be greater than 40IU/L. when the result of serum gonadotropin is elevated, there is the need to repeat the assay several months apart. High Gonadotropins: Rarely tumours produce gonadotropins, as occurs in cancer of the lung. However, due to its rarity a good history and physical examination, precludes a routine chest x-ray for all amenorrheic women. It is necessary to assay for both gonadotropins, so as to be able to diagnose the rare single gonadotropin deficiency (diagnosed by a high level of one and the baseline or undetectable level of the other gonadotropins). Note: an elevated FSH level is not an absolute indicator of infertility. It is not unusual to encounter a pregnancy in a woman after a diagnosis of premature ovarian failure. All patients with premature ovarian failure should be tested for complete thyroid function test including antibodies. Other rare conditions associated with premature ovarian failure includes myasthenia gravis, idiopathic thrombocytopenic purpura, rheumatoid arthritis, vitiligo, and autoimmune haemolytic anaemia. Classically, premature ovarian failure precedes adrenal failure, hence there is the need for continued adrenal surveillance. Galactosemia is a rare inherited autosomal recessive disorder of galactose metabolism due to a deficiency of galactose-1phosphate uridyl transferase. The problem in galactosemia is primarily gonadal; fewer oogonia may be the result of a direct toxic effect of galactose metabolites on germ cell migration to the genital ridge. Premature ovarian failure is common and usually irreversible. A final rare clinical condition associated with high gonadotropin, despite the presence of ovarian follicle is the enzymatic deficiencies such as 17- hydroxylase deficiency which usually affects ovaries and the adrenal gland. This is usually detectable due to absence of secondary sexual development (sex steroids cannot be produced due to the enzyme block in the adrenal glands and the ovaries), and hypertension, hypokalemia, and high blood levels of progesterone.

The need for chromosome evaluation: All patients under the age of 30 diagnosed to have ovarian failure on the basis of elevated gonadotropins must have a karyotype determination. The presence of mosaicism with a Ychromosome requires the excision of the gonadal area, since the presence of these gonad is associated with malignant tumour (germ cell tumour such as gonadoblastomas, dysgerminomas, yolk sac tumours, and choriocarcinoma. Approximately 30% of patients with Y-chromosome will not develop signs of virilization, therefore, even the normal appearing adult woman with elevated gonadotropin levels must be karyotyped. Note: even if the karyotype is normal, all patients with premature ovarian failure should have an annual pelvic examination (a precautionary measure). Over the age of 30, amenorrhea with high gonadotropin is best labelled premature menopause. Accurate diagnosis of X-chromosome deletions on karyotype reveals there is a family history of infertility due to premature ovarian failure, which can influence the family planning decisions of family members. Premature ovarian failure: (A clinical dilemma) Patients with repeatedly elevated gonadotropin levels can be reliably diagnosed as having ovarian failure and can be considered sterile. However, 10-20% of patient presenting with secondary amenorrhea and elevated gonadotropin (with normal karyotypes), have had spontaneous recovery, with return of normal function and have been able to achieve pregnancy. A number of premature ovarian failure are due to autoimmune disorders – therefore during evaluation do selected blood test for autoimmune disease. • Calcium • Phosphorus • Fasting glucose • A.M. cortisol • Free T4 • TSH • Thyroid antibodies, if thyroid function is abnormal • Complete blood count and ESR • Total protein; albumin: globulin ratio • Rheumatoid factor • Antinuclear antibody

Periodic surveillance for adrenal failure is in order because ovarian failure usually precedes adrenal failure. Other than hypothyroidism, it is uncommon to encounter other disorders associated with premature ovarian failure. Normal Gonadotropins: FSH and LH levels in the normal range in a patient with hypoestrogen, resulting in a negative progestational withdrawal test are consistent with pituitary-CNS failure. Extremely low or undetectable gonadotropins are seldom found, usually only with large pituitary tumours or in patients with anorexia nervosa. Low Gonadotropins: If the gonadotropins are abnormally low, or in the normal range in a patient with amenorrhea, it would be necessary to evaluate the sella turcica by imaging for signs of abnormal change to distinguish between a pituitary (compartment III) or CNShypothalamic (compartment IV) cause for amenorrhea. Imaging the sella turcica: The diagnostic modality of choice is either thin – section coronal CT scan with intravenous contrast enhancement or MRI with gadolinium enhancement. MRI is more sensitive than CT-scan, but more expensive. CT-scan is able to evaluate the contents of the sella turcica as well as the suprasellar area. If the prolactin level is greater than 100ng/ml, or if the coned down x-ray view of the sella turcica is abnormal then CT-scan or MRI would be necessary. The presence of visual problems and/or headaches should also encourage CT-scan or MRI evaluation. Headaches are definitely correlated with the presence of a pituitary adenoma – headaches are usually bifrontal, retroorbital or bitemporal. Hypogonadotropic hypogonadism: Patients with amenorrhea, but no galactorrhea and have normal imaging studies are classified as hypothalamic amenorrhea. The mechanism resulting in hypothalamic amenorrhea is suppression of pulsatile GnRH secretion below its critical range. It is a diagnosis by exclusion; we can identify probable causes – anorexia and weight loss. Specific Disorders within Compartments: Compartment 1: disorders of the outflow tract or uterus

Asherman’s syndrome This condition generally follows overzealous postpartum curettage, resulting in intrauterine scarification. It may also occur following uterine surgery, including Caesarean section, myomectomy, or metroplasty. It as also been noted following Sheehan’s syndrome (postpartum hypogonadism). Patients with Asherman’s syndrome, besides amenorrhea can present with miscarriages, dymenorrhea, or hypomenorrhea. They can even have normal menses. Infertility can be present with mild adhesions. Patients with repeated miscarriages, infertility, or pregnancy wastage should have investigation of the endometrial cavity by hysterogram or hysteroscopy. In Asherman’s a typical partern of multiple synechiae is seen on a hysterogram (HSG) – filling defects. The gold standard for diagnosis is hysteroscopy, which is more accurate and can detect minimal adhesions that are not apparent on HSG. In the presence of normal ovarian function, the basal body temperature will be biphasic. The adhesion may partially or completely obliterate the endometrial cavity, the internal cervical os, the cervical canal or combinations of these areas. Surprisely, despite stenosis or atresia of the internal cervical os, haematometra does not inevitably occur – may be perhaps, the endometrium in response to a buildup of pressure, becomes refractory, and simple cervical dilatation cures the problem. Impairment of the endometrium resulting in amenorrhea can be caused by tuberculosis, the diagnosis is made by culture of the menstrual discharge or endometrial biopsy. Amenorrhea may also occur in the presence of uterine schistosomiasis and diagnosis is made by finding parasite eggs in urine, faeces, rectal scrapings, menstrual discharge, or endometrial biopsy. Asherman’s syndrome may also follow pelvic infection with IUCD in-situ or severe PID. Management: dilatation and curettage to break up adhesions, after which an IUCD is inserted to prevent re-apposition of the uterine wall, with consequent adhesions. A paediatric Foley catheter appears a better option for preventing repeat adhesion formation the balloon is filled with 3ml of fluid and removed after 7 days. Preoperatively a broad spectrum antibiotics is started and maintained for 10 days. An inhibitor of prostaglandin synthesis can be used if uterine cramping becomes a problem.

The patient following adhesiolysis is treated for 2 months with high stimulatory doses of oestrogen (e.g. conjugated oestrogens 2.5mg daily for 21 days (i.e for 3 weeks) and medroxyprogesterone acetate 10mg daily is added thereafter to induce withdrawal bleeding, if the initial treatment fails to reestablish menstrual flow, the treatment is repeated. About 70-80% of patients with this condition have achieved pregnancy with treatment. However, pregnancy is frequently complicated by premature labour, placenta acreta, placenta praevia, and/or postpartum haemorrhage. Müllerian anomalies In primary amenorrhea, segmental discontinuity of the mullerian tube should be ruled out by direct observation – imperforate hymen, obliteration of the vaginal orifice (transverse vaginal septum). The cervix or the entire uterus may be absent. Far less common, the uterus may be present, but the cavity absent, or, in the presence of the cavity, the endometrium may be congenitally absent. With the exception of the latter abnormalities, the clinical problem of amenorrhea due to obstruction is compounded by painful distension of haematocolpos, haematometra, or haemoperitoneum. In all instances, an effort must be made to incise and drain from below at the point of closure of the mullerian tube. Müllerian agenesis Lack of müllerian development (Mayer-Rokitansky-KusterHauser syndrome) is the diagnosis for the individual with primary amenorrhea and no apparent vagina. This is a relatively common cause of primary amenorrhea (about 1 in 4000 female births), second only to gonadal agenesis. These patients have an absence or hypoplasia of the internal vagina, and usually an absence of the uterus and fallopian tubes. However, rarely, the uterus may be normal, but lacking a conduit to the introitus, or there may be only rudimentary, bicornuate cords present. If a partial endometrial cavity is present, cyclic abdominal pain may be a complaint. This condition is similar to some types of male pseudohermaphroditism, therefore, it is necessary to demonstrate normal female karyotype. The ovaries are not mullerian structures and so function normally and can be documented by normal basal body temperature or peripheral levels of progesterone. Growth and development are normal. The exact cause of mullerian agenesis is unknown. Likely causes are mutation in the gene for antimullerian hormone or the gene for the antimullerian hormone receptor. The underlying mechanism would be unwanted exposure to

antimullerian hormone activity. Although usually sporadic, occasional occurrence may be noted within a family. A mutation has been noted in mothers with galactose-1phosphate uridyl transferase in which mothers and daughters have mullerian agenesis. For patient with mullerian agenesis further evaluation should include radiologic studies. Approximately one-third of patients have urinary tract abnormalities (ectopic kidney, renal agenesis, horseshoe kidney and abnormal collecting ducts) and 12% or more have skeletal anomalies, most involving the spine, although absent digits and syndactyly (webbing or fusion of fingers or toes) can occur. When the presence of a uterine structure is suspected on examination, USS can be utilized to depict the size and symmetry of the structure. When uncertain with ultrasound, then MRI would be used for evaluation. Laparoscopy for visualizing the pelvis may not be necessary. Extirpation of the mullerian remnants is certainly not necessary unless they are causing a problem such as uterine fibroid growth, haematometra, endometriosis, or symptomatic herniation into the inguinal canal. Management options Progressive dilatation Surgical construction of the vagina Transverse vaginal septum is a failure of canalization of the distal third of the vagina, usually presents with symptoms of obstruction and urinary frequency. A transverse septum can be differentiated from an imperforate hymen by a lack of distension at the introitus with valsalva’s manoeuvre. Distal obstruction of the genital tract is the only condition in this category that can be considered an emergency. Delay in surgical treatment can lead to infertility due to inflammatory changes and endometriosis. Definitive surgery should be accomplished as soon as possible. Diagnostic needling should be avoided because a haematocolpos can be converted into a pyocolpos. Genetic offspring can be achieved by collection of oocytes from the genetic mother, fertilization by the genetic father, and placement into a surrogate carrier. Androgen insensitivity (testicular feminization):

Complete androgen insensitivity results in a blind short vaginal canal, with absent uterus. This is the 3rd most common cause of primary amenorrhea. The patient is a male pseudohermaphrodite, has gonadal sex(XY), therefore the individual has testes and an XY karyotype. The patient is a phenotypic female, with absent or sparse pubic and axillary hair. There is absence of virilization. This disorder is X-linked recessive. Clinically the diagnosis should be considered in a female child with inguinal hernia, because the testes are frequently partially descended, a patient with primary amenorrhea and an absent uterus, or a patient with absent body hair. These patients appear normal at birth except for the possible presence of an inguinal hernia, and most patients are not seen by a physician until puberty. Growth and development are normal, although overall height is usually greater than average, and there may be a eunuchoidal tendency (long arms, big hands, and big feet). The breast, although large, are abnormal: actual glandular tissue is not abundant, nipples are small, and the areolae are pale. More than 50% have an inguinal hernia, the labia minora are usually underdeveloped, and the blind vagina is less deep than normal. There may be rudimentary fallopian tubes composed of fibromuscular tissue with only occasional epithelial lining. Horseshoe kidneys have been reported. The testis may be intra-abdominal, but often are within the groin in the hernia. They may be nodular. After puberty testis display an immature tubular development, and tubules are lined by immature germ cells and Sertoli cells. There is no spermatogenesis, and the incidence of neoplasia within these gonads is high. Therefore, once full development is attained after puberty, the gonads should be removed at approximately 16-18yrs, and patient placed on hormone therapy (this is the only exception to the rule, that gonads with Y chromosome should be removed as soon as diagnosis is made). There are 2 reasons for this exception – first, the development achieved with hormone replacement does not seem to match the smooth pubertal changes due to endogenous hormones, and second, gonadal tumours in these patients have not been encountered prior to puberty. The removal of these gonads can be accomplished through the laparoscope, reserving the option of laparotomy if the gonads are inaccessible.

In testicular feminization, the urinary 17-ketosteroids are normal, the plasma testosterone is within the range of high normal male values, and the plasma clearance and metabolism of testosterone are normal. Therefore, these patient do not respond to androgens, either their own or those given locally or systemically. Therefore, the critical steps in sexual differentiation, which require androgens, fail to take place, and development is totally female. Because antimullerian hormone is present, development of the mullerian duct is inhibited, hence the absence of uterus, tubes, and upper vagina. This syndrome is marked by a unique combination: 1. Normal female phenotype. 2. Normal male karyotype, 46, XY. 3. Normal or slightly elevated male blood testosterone levels and a high LH. Incomplete androgen insensitivity: one-tenth as common as the complete syndrome. The individuals have some androgen effect on the end-organ. These individual may have clitoral enlargement, or a phallus may even be present. Axillary hair and pubic hair develop along with breast growth. Gonadectomy should not be deferred in such cases because it will obviate unwanted further virilization. Patients with a deficit in testicular 17β-hydroxysteroid dehydrogenase activity will have impaired testosterone production and present clinically as incomplete androgen insensitivity. Because treatment (gonadectomy) is the same, precise diagnosis is not essential. In the past, conventional wisdom warned against unthinking and “needless” disclosure of the gonadal and chromosomal sex to a patient with complete androgen insensitivity. This attitude has changed as, more and more, patients desire and appreciate a full understanding of themselves. Although infertile, these patients are certainly completely female in their gender identity, and this should be reinforced rather challenged. What is strongly advocated is combining a truthful education with appropriate psychological counselling of patients and parents. Compartment II: Disorders of the Ovary Gonadal developmental problems can present with either primary or secondary amenorrhea.

30-40% of cases with primary amenorrhea, are due to gonadal streaks (resulting from abnormal development): the incidence of the karyotypes in this group are – • 50% - 45, X • 25% - mosaics • 25% - 46, XX Women with gonadal dysgenesis can also present with secondary amenorrhea. The karyotypes associated with this presentation are, in order of decreasing frequency: • 46, XX (most common). • Mosaics (e.g., 45, X/46, XX). • Deletions in X short and long arms. • 47, XXX • 45, X Both X chromosome must be present and active in oocytes to avoid the accelerated loss of follicles. Perrault syndrome comprises gonadal dysgenesis, with normal karyotype and also linked with neurosensory deafness – hence, auditory evaluation should be considered in any patient with gonadal dysgenesis and 46, XX. Pure gonadal dysgenesis indicates the presences of bilateral streak gonads, regardless of the karyotype. Mixed gonadal dysgenesis indicates the presence of testicular tissue on one side and a streak gonad on the other side. Turner syndrome: 45, X They are short statured, webbed neck, shield chest, and an increased carrying angle at the elbow, combined with hypergonadotropic hypoestrogenic amenorrhea. The above finding makes the diagnosis on clinical evaluation possible. As a result of the absent ovarian follicles, there is no gonadal sex hormone production at puberty, and thus patient presents with primary amenorrhea. Always rule out autoimmune disorders, cardiovascular and renal abnormalities. The karyotype must be performed on all patients with elevated gonadotropins, inspite of the presence of phenotypic trait of Turner syndrome. Mosaicism: Mosaicism is the presence of multiple cell lines of varying sex chromosome composition (e.g 45, X/46, XY or 45, X/46, XX) in an individual. This must be ruled out in patient with

amenorrhea, because of the need to exclude the presence of Y chromosome in cases of gonadal dysgenesis; which should necessitate gonadectomy – the presence of any testicular component in the gonadal area predispose to tumour formation and to heterosexual development (virilization). Only in patient with complete androgen insensitivity is gonadectomy deferred until after puberty, since the individual is resistant to androgens and gonadal turmours occur late. Approximately 30% of patients with a Y chromosome will not develop signs of virilization. Therefore, even the normalappearing adult patient with elevated serum gonadotropins must have their karyotype done, to detect a silent Y chromosome so that prophylactic gonadectomy can be performed before neoplastic changes occur. The impact of mosaicism, even in the absence of a Ychromosome is significant. With an XX component (e.g. XX/XO), functional ovarian tissue can be found within the gonad, leading to a variety of responses, including some degree of female development, and, on occasion even menses and reproduction. These individuals may appear normal, attaining normal stature before premature menopause is experienced. Note: All patients with absent ovarian function and quantitative alterations in the sex chromosomes are categorized as having gonadal dysgenesis. XY Gonadal dysgenesis: A female patient with XY karyotype, who has a palpable mullerian system, normal female testosterone levels, and lack of sexual development has Swyer’s syndrome. Tumour transformation in the gonadal ridge can occur at any age. Therefore, gonadectomy should be performed as soon as the diagnosis is made. Gonadal agenesis: Gonadal failure due to agenesis, does not result in any complicated clinical problems. Hypergonadotropic hypogonadism, in the absence of gonadal function, development is female. Surgical removal of the gonadal streaks is necessary to avoid the possibility of neoplasia. Viral or metabolic influence in early gestation or undiscovered genetic mutations may be responsible. The Resistant Ovary syndrome: This is a rare presentation, the patient has amenorrhea, normal growth and development, with elevated gonadotropins despite the presence of unstimulated ovarian follicles, there is no evidence of autoimmune disease. Laparotomy is necessary to

arrive at a correct diagnosis by obtaining adequate histological evaluation of the ovaries – it demonstrates not only the presence of follicles but absence of the lymphocytic infiltration seen with autoimmune disease. Because of the rarity of this condition and the very low chance of achieving pregnancy even with high doses of exogenous gonadotropins, it may not be necessary to perform laparotomy, for the purpose of ovarian biopsy on every patient with amenorrhea, high gonadotropins, and a normal karyotype. These patients are excellent candidates for oocyte donation. Premature Ovarian failure: This is the early depletion of ovarian follicles before the age of 40 yrs. The aetiology of premature ovarian failure is unknown is most cases. However, the aetiological factors include chromosomal anomalies (the most common anomalies are 45, X and 47, XXY followed by mosaicism), autoimmune diseases, infections (mumps oophoritis), physical assault of the ovaries such as chemotherapy and irradiation. Premature ovarian failure is surprisingly common, approximately 1% of women will experience ovarian failure before the age of 40, the incidence is higher in women with primary amenorrhea (prevalence ranges from 10-28%). Premature ovarian failure can present at any age: if lose of follicles has been rapid, then primary amenorrhea and absence of secondary sexual characteristics will be present. If loss of follicles occurred during or after puberty, then the extent of adult phenotypic development and the time of onset of secondary amenorrhea will vary accordingly. There as been reports of spontaneous resumption of normal ovarian function, in 10-20% of patient with normal karyotype, with premature ovarian failure. Therefore, one cannot be certain that patient with premature ovarian failure will be sterile forever. Management: Laparotomy with a full thickness ovarian biopsy may not be necessary in all cases, a survey for autoimmune diseases (recognizing that there is no practical clinical method to accurately diagnose autoimmune ovarian failure) and an assessment of ovarian-pituitary activity, is sufficient. As with other hypogonadal state, hormone therapy is recommended. However, because of spontaneous ovulations that can occur, an oral contraceptive is a better treatment regimen of choice if pregnancy is not desired. The best prospect for pregnancy in those with premature ovarian failure is oocyte donation (note, pregnancy rates are reduced, if sibling’s donated oocytes are used). The effect of Radiation and Chemotherapy;

The effect of radiation on ovarian function is dependent upon the age and the x-ray dose. Steroid levels begin to fall and gonadotropins (FSH, LH) rise within 2 weeks after irradiation to the ovaries. The higher number of oocytes in younger age is responsible for the resistance to total castration in young women exposed to intense radiation. Function can resume after many years of amenorrhea. On the other hand, the damage may not appear until later in the form of premature ovarian failure. If pregnancy does occur, the risk of congenital abnormalities is not greater than normal population. When the irradiation field excludes the pelvis, there is no risk of premature ovarian failure. For this reason, elective transposition of the ovaries by laparoscopy out of the pelvis, prior to irradiation provides a good prospect for future fertility. Gonads are not in danger in the kitchen; microwave ovens utilize wavelength with low tissue-penetrating power. OVARIAN DOSE 60rads 150rads 250-500rads 500-800rads Over 800rads

STERILIZATION EFFECT No effect Some risk over age 40 Ages 15-40: 60% sterilized Ages 15-40: 60-70% sterilized 100% permanently sterilized Alkylating agents are very toxic to the gonads. There is an inverse relationship between the dose required for ovarian failure and the age at the start of therapy. Other chemotherapeutic agents have the potential for ovarian damage, have been less studied. The effect of combination chemotherapies is similar to those of the alkylating agents. Approximately 2/3rd of premenopausal women with breast cancer and treated with cyclophophamide, methotrexate, and fluorouracil lose ovarian function. Resumption of menses and pregnancy can occur, but there is no way to predict which patient will reacquire ovulatory function. The damage may present late with premature ovarian failure. The harvesting and cryopreservation of oocytes prior to irradiation and/or chemotherapy will ultimately prove to be the best means of preserving fertility for these patients. Compartment III: Disorders of the Anterior Pituitary: 1. Pituitary tumours: malignant tumours of the pituitary are very rare, most are benign and cause problem by their growth (expansion) in a confined space. The tumour grows upward, compressing the optic chiasma and producing the classic findings of bitemporal hemianopsia,

with small tumours, however, abnormal visual fields are rarely encountered. 2. Other tumours of this region (e.g. craniopharyngioma, usually marked by calcifications on x-ray) may be associated with the early development of blurring of vision and visual field defects because of their close proximity to the optic chiasma. Other very rare tumours include meningiomas, gliomas, metastatic tumours, and chordomas. • Increased melatonin secretion, probably from a cystic pineal lesion, has been reported as a cause of delayed puberty. • Hypogonadism and delayed puberty deserves brain evaluation by MRI Situations of increased suspicion of pituitary tumours: • Acromegaly caused by excessive secretion of growth hormone, if suspected, growth hormone should be measured during an oral glucose tolerance test (a lack of suppression of growth hormone levels is diagnostic), and the circulating level of insulin growth factor-1 should be measured. • Cushing’s disease due to excessive secretion of ACTH, if clinical criteria suggest Cushing’s disease, ACTH levels and the 24-hr urinary level of free cortisol should be measured, and a rapid suppression test (dexamethasone test) for confirmation. • Rarely, a TSH-secreting tumour will cause secondary hyperthyroidism. Amenorrhea and/or galactorrhea may precede the eventual full clinical expression of a tumour that secretes ACTH or growth hormone. Note: the 2 most common pituitary tumours are prolactin-secreting adenomas and the clinically nonfunctioning tumours. Acromegaly can initially present with an elevated prolactin level and amenorrhea, therefore, the circulating level of IGF-1 should be measured in all patients with a macroadenoma (> 10mm diameter). Non-functioning pituitary tumours: (30-40% of all pituitary tumours) Majority of the non-functioning pituitary tumours are of gonadotroph origin and actively secrete FSH, free α-

subunit, and rarely, LH – these hormones do not have clinical effects. The symptoms in patient, with nonfunctioning tumours are the result of space occupying lesion. The α-subunit can be used as a tumour marker, in conditions of non-functioning tumour. However, in postmenopausal women (the age at which most gonadotroph adenomas manifest), the use of α-subunit as tumour marker is confusing since in this menopausal period, there is hypergonadotropins which is accompanied with increased α-subunit. Patients with pituitary tumour which is secreting gonadotropins, do not down-regulate gonadotropin secretion in response to GnRH agonist treatment, and repeated GnRH agonist administration is associated with persistent elevations in either FSH or α-subunit. However, most patients with these tumours, have reduced secretions of gonadotropins (and amenorrhea) because of tumour compression of the pituitary stalk and interference with the delivery of hypothalamic GnRH, these patients also often present with modest elevation of prolactin (due to the inability of dopamine to reach the anterior pituitary). Other causes of pituitary compression (non-neoplastic): Cyst , tuberculosis, sarcoidosis, and fat deposits in the intrasellar area are causes of pituitary compression leading to hypogonadotropic amenorrhea. Lymphocytic hypophysitis is a rare autoimmune infiltration of the pituitary gland that can mimic a pituitary tumour, often occurring during pregnancy or in the first 6 months postpartum. In the initial phase of hypophysitis, hyperprolactinaemia is common, followed by hypopituitarism. Transsphenoidal surgery is both diagnostic and therapeutic for this potentially lethal condition. Nearby lesions, such as internal carotid artery aneurysms and obstruction of the aqueduct of Sylvius, can also cause amenorrhea. Pituitary insufficiency can be secondary to ischaemia and infarction, which is a late sequel of obstetric haemorrhage – Sheehan’s syndrome.

Symptoms of hypopituitarism are usually seen early in the postpartum period, especially failure of lactation and loss of pubic and axillary hair. Deficiencies in growth hormone and gonadotropins are most common, followed by ACTH, and last, by TSH in frequency. Diabetes insipidus is not usually present. This condition can be life-threatening. Other rare causes of amenorrhea are LaurenceMoon-Biedl and Prader-Willi syndrome. Treatment of Non-functioning Adenomas: Asymptomatic patient with microadenoma (less than 10mm in diameter), usually do not need treatment, follow up imaging is recommended in a year or two to be sure it is no growing. Usually they are incidental finding. If a macroadenoma (greater than 10mm in diameter), is present in a patient and symptomatic, surgery is necessary; these tumours are commonly detected following the onset of symptoms (headaches and visual disturbances). Adjunctive irradiation may be necessary if residual tumour and elevated gonadotropins and α-subunit are present after surgery to reduce the risk of recurrence. Follow-up imaging is obtained every 6 months for 1 year, and then yearly for 3-5years. The risk of hypopituitarism increases with irradiation, therefore ongoing surveillance of adrenal and thyroid function is necessary. Pituitary prolactin-secreting adenomas: These are the most common pituitary adenomas. Serum prolactin level of 1000ng/ml are associated with invasive tumour, which are effectively treated with dopamine agonist (bromocriptine). Approximately one-third of women with galactorrhea have normal menses. As the prolactin concentration increases, a woman can progress sequentially from normal ovulation to an inadequate luteal phase to intermittent anovulation to total anovulation to complete suppression and amenorrhea. The clinical symptoms do not always correlate with the prolactin level, and patients with normal prolactin levels can have pituitary tumours. The

highest serum prolactin levels, however, are associated with amenorrhea, with or without galactorrhea. The amenorrhea associated with elevated prolactin levels is due to prolactin inhibition of the pulsatile secretion of GnRH. Dopamine agonist treatment: Bromocriptine is a lysergic acid derivative with a bromine substitute at position 2. it is available as 2.5mg tablets. The usual average dose is 5-7.5mg daily. This is usually achieved by starting with low dose to gradually develop tolerance to the drug – 2.5mg daily at bed time, for about a week, before increasing to bid (at breakfast or lunch). This dose may need to be taken for a long time, by the response is dramatic, with improvement in headache, visual disturbance, menstrual cycle, ovulation and galactorrhea. Side effects of bromocriptine – nausea, headache, faintness (due to orthostatic hypotension, which is attributed to relaxation of smooth muscle in the splanchnic and renal beds) Route of administration: Oral – 28% of the drugs are absorbed, 94% of the drugs absorbed undergo extensive 1st pass effect in the liver. Excretion is mainly biliary. The oral slow release tablets is 5-15mg daily. Intramuscular injections – depot-bromocriptine in a dose of 50-75mg monthly. Bromocriptine tablets – can be administered through the vaginal route, it reduces the side effects, and avoid the 1st pass effect in the liver, with the result of longer maintenance systemic levels, allow achievement of therapeutic results at a lower dose. One tablet of 2.5mg is inserted high into the vagina at bedtime. The absorption from the vagina is nearly complete. It is important to advise patients that the cessation of galactorrhea is a slower and less certain response than restoration of ovulation and menses. Other Dopamine agonists:

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Pergolide is more potent, longer lasting, and better tolerated by some patient. It is given in a single daily dose of 50-150mg, it is effective for bromocriptine resistant patient. Quinagolide – given in a daily bedtime dose of 75-300mg. Cabergoline given orally at doses of 0.5 to 3.0 mg once weekly.

Summary of pituitary prolactin-secreting adenomas: Macroadenomas: Currently, dopamine agonist treatment is advocated for the treatment of macroadenomas, utilizing as low a dose as possible. Shrinkage of a tumour may require 5-10 mg of bromocriptine daily, but once shrinkage has occurred, the daily dose should be progressively reduced until the lowest maintenance dose is achieved. The serum prolactin level can be used as a marker, checking every 3 months until stable. Withdrawal of the drug is usually associated with regrowth or reexpansion of the tumour, and, therefore, treatment must be long-term, if not indefinite. The failure of a tumour to shrink significantly in size despite a normalization of prolactin levels is consistent with a non-functioning tumour that is interrupting the supply of dopamine to the pituitary by stalk compression. Early surgery is indicated. Microadenomas: The treatment is directed to solve one of 2 problems: infertility or breast discomfort. The treatment of choice is dopamine agonist. Other modalities for treating pituitary prolactin-secreting adenomas include surgery through the transsphenoidal approach or irradiation. Other causes of pituitary amenorrhea includes: • Empty sella syndrome – could be congenital, secondary to surgery, radiotherapy, or infarction of a pituitary tumour. This condition is benign; it does not progress to pituitary failure. Compartment IV: Central nervous system disorders. Hypothalamic amenorrhea (hypogonadotropic hypogonadism):

Patients with hypothalamic amenorrhea have a deficiency in GnRH pulsatile secretion. Hypothalamic problems are usually diagnosed by excluding pituitary lesions. Most hypothalamic amenorrhea are associated with stressful events. The degree of GnRH suppression determines how these patient present clinically. Mild suppression can be associated with a marginal effect on reproduction, specifically an inadequate luteal phase. Moderate suppression of GnRH secretion can yield anovulation with menstrual irregularity, and profound suppression is manifested by hypothalamic amenorrhea. Patients with hypothalamic amenorrhea are categorized by low or normal gonadotropins, normal prolactin levels, a normal imaging evaluation of the sella turcica, and a failure to demonstrate withdrawal bleeding. Women with hypothalamic amenorrhea have reduced secretion of FSH, LH, and prolactin, but increased secretion of cortisol. It is important to assure these patient that, at the appropriate time, treatment for the induction of ovulation will be available and that fertility can be achieved. Induction of ovulation should only be performed for the purpose of producing a pregnancy. Causes of hypothalamic amenorrhea • Weight loss – anorexia, Bulimia • Exercise

Diagnosis of Anorexia nervosa 1. onset between ages 10 and 30 years. 2. weight loss of 25% or weight 15% below normal for age and height. 3. special attitudes:  denial,  distorted body image,  unusual hoarding or handling of food. 4. at least one of the following;  lanugo hair,  bradycardia,  overactivity,  episodes of overeating (bulimia),  vomiting, which may be self-induced.

5. 6. 7. 8.

amenorrhea no known medical illness. no other psychiatric disorder. other characteristics:  constipation,  low blood pressure,  hypercarotenemia,  diabetes insipidus.

Other causes of amenorrhea acting through the CNS • Exercise – when training starts before menarche, menarche can be delayed as much as 3 years, and the subsequent incidence of menstrual irregularities is higher. Contrary to the female situation, exercise has little effect on the timing of puberty in boys. • Kallmann’s syndrome – deficient secretion of GnRH, associated with anosmia or hyposmia. In the female, this is characterized by primary amenorrhea, infantile sexual development, low gonadotropins, a normal female karyotype, and the inability to perceive odours; e.g., coffee grounds or perfume. The gonads can respond to gonadotropins, therefore induction of ovulation with exogenous gonadotropins is successful. However, clomiphene is ineffective.