Hypogonadotropic hypogonadism

1. Hypogonadotropic hypogonadism Dr Zahra Ghasemzade January 2019

2. Agenda • Definition • Hypothalamic (CDGP, FHA,IHH or IGD, Tumor, infection, infiltrative process, trauma ,chemotherapy or radiation) • Hypophysial (Lymphocytic hypophysitis ,Sheehan syndrome , Empty Sella Syndrome , Pituitary Apoplexy , tumor ,…)

3. Menarche usually occurs in the 6-month period preceding or following the fusion of the second and first distal phalanges and the appearance of the sesamoid bone; this corresponds to Tanner stage 4 in most cases. • The 95th percentile for menarche is 14.5 years, although many textbooks define primary amenorrhea as absence of menses at 16 years. • The upper limits of the normal age of onset of puberty are 13 years for girls

5. Constitutional Delay in Growth and Puberty • healthy girls who spontaneously enter puberty after the age of 13 years, the most common diagnosis for delayed puberty. • Affected individuals usually are short (2 SD below the mean value of height for age) at evaluation and have been shorter than their classmates for years, although growth velocity and height are usually appropriate for bone age. • Family history in as many as 77% of cases reveals a mother who had delayed menarche or a father (or sibling) who entered puberty late , and the pattern in some cases suggests dominant inheritance with incomplete penetrance. • Because of delay in reactivation of the GnRH pulse generator, there is functional deficiency of GnRH for chronologic age but not for the stage of physiologic development. • Adrenarche and gonadarche occur later in individuals with CDGP

6. FHA is a form of chronic anovulation that is not due to identifiable organic causes   • Low energy availability (from decreased caloric intake, excessive energy expenditure, or both) and stress are common causes of hypogonadotropic hypogonadism in women. • . FHA is presumed to be a functional disruption of pulsatile GnRHsecretion. • The abnormal GnRH secretion characteristic of FHA leads to decreased pulses of gonadotropins, absent midcycle surges in LH secretion, absence of normal follicular development, anovulation, and low serum estradiol (E2) concentrations. Variable neuroendocrine patterns of LH secretion can be seen. • Serum concentrations of FSH are low or normal, and they often exceed those of LH, similar to the pattern in prepubertal girls.

7. The overall prevalence of functional hypothalamic amenorrhea among all amenorrhea disorders ranges from 15% to 48% • LH pulse frequency is used as a surrogate measure to evaluate GnRH secretion because each GnRH pulse is accompanied by a concomitant LH pulse. • A key observation in functional hypothalamic anovulation is the absence of increased gonadotropin secretion despite the lack of inhibitory factors of ovarian origin, such as estradiol and inhibin • There is variability in the amplitude and frequency of the pulsatile LH secretion in women with functional hypothalamic amenorrhea.

8. Anorexia nervosa • Refusal to maintain body weight at or above a minimally normal weight for age and height (e.g. weight loss leading to maintenance of body weight less than 85% of that expected; or failure to make expected weight gain during period of growth, leading to body weight less than 85% of that expected). • Intense fear of gaining weight or becoming fat, even though underweight. • Disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight. • In postmenarcheal females, amenorrhoea, i.e. the absence of at least three consecutive menstrual cycles.

9. Diagnosis, differential diagnosis • We suggest that clinicians only make the diagnosis of functional hypothalamic amenorrhea (FHA) after excluding the anatomic or organic pathology of amenorrhea. • We suggest diagnostic evaluation for FHA in adolescents and women whose menstrual cycle interval persistently exceeds 45 days and/or those who present with amenorrhea for 3 months or more. • We suggest screening patients with FHA for psychological stressors (patients with FHA may be coping with stressors, and stress sensitivity has multiple determinants). • We suggest clinicians inform patients that irregular menses do not require immediate evaluation and that menstrual irregularity does not preclude conception.

10. Evaluation • we recommend obtaining a detailed personal history with a focus on diet ; eating disorders; exercise and athletic training; attitudes, • Weight fluctuations; sleep patterns; stressors; mood; menstrual pattern; fractures; and substance abuse. • In a patient with suspected FHA, we recommend excluding pregnancy and performing a full physical examination, including a gynecological examination to evaluate the possibility of organic etiologies of amenorrhea. • we recommend obtaining the following screening laboratory tests: B-HCG, CBC, electrolytes, glucose, bicarbonate, BUN, creatinine, liver panel, and (when appropriate) ESR and/or CRP levels. • As part of an initial endocrine evaluation for patients with FHA we recommend obtaining the following laboratory tests : TSH, free T4, prolactin, FSH, estradiol (E2), and AMH. • We recommend a brain MRI (with pituitary cuts and contrast) in adolescents or women with presumed FHA and a history of severe or persistent headaches; persistent vomiting that is not self-induced; change in vision, thirst, or urination not attributable to other causes; lateralizing neurologic signs; and clinical signs and/or laboratory results that suggest pituitary hormone deficiency or excess.

11. Miscellaneous Disorders • Diabetes mellitus • Cushing disease • Hyperprolactinemia • Sickle cell disease • Cystic fibrosis • Acquired immunodeficiency syndrome (AIDS) • Chronic gastroenteric disease • Chronic renal disease • Marijuana use , opioids, anabolic steroids • Prader-Willi syndrome ( hypotonia, short stature, mild mental retardation) • Laurence-Moon and Bardet-Biedl syndromes (Obesity, pigmentary retinopathy, polydactyly, mental retardation and renal failure)

12. Idiopathic hypogonadotropic hypogonadism (IHH) • Isolated gonadotropin-releasing hormone deficiency (IGD), or idiopathic hypogonadotropic hypogonadism (IHH), is defect involving the GnRH pulse generator (production and/or action) or gonadotrophs without an anatomic lesion causes selective deficiency of gonadotropins, • IHH can occur either with normal olfaction (normosmic IHH) or with anosmia. • this disorder is characterized by inappropriately low or normal serum concentrations of LH and FSH in the setting of prepubertal levels of gonadal steroids. • more than two-thirds of IHH patients appear to be sporadic • family history of anosmia; the absence of menstrual periods; delayed puberty; or the presence of skeletal, renal, or cardiac abnormalities associated with various genetic forms of GnRH deficiency

14. Clinical Presentation • 1 of every 40,000 females . •  There is a relatively broad spectrum of clinical expression that can occur in IHH, ranging from complete absence of sexual development to partial completion of puberty that does not subsequently progress. • At puberty, patients present with a complete form of IHH that is characterized by a failure to initiate sexual maturation (lack of secondary sexual characteristics, primary amenorrhea in girls, and failure to establish a pubertal growth spurt). • There are specific genotype-phenotype relationships, unilateral renal agenesis and synkinesia (mirror movements) appeared to be phenotypic markers for the X-linked form of KS. synkinesiahas also been reported in autosomal dominant forms of IHH as well . • phenotype-genotype correlations: dental agenesis and digital bony abnormalities (FGF8/FGFR1), and hearing loss (CHD7, SOX10, IL17RD)

15. Physical findings General appearance • The body habitus of adolescent patients failing to undergo puberty often is eunuchoidal, with arm span exceeding height by 5 cm or more(The mean U/L segment ratio of white adults is 0.92, and that of African-American adults is 0.85. decreased U/L segment ratio) . This finding reflects the delayed closure of the epiphyses of long bones caused by hypogonadism and lack of sex steroid production during puberty. • secondary sexual characteristics are often completely absent, with little or no breast development . • some pubic hair can be present because adrenarche, with its concomitant small amounts of adrenal androgen and estrogen secretion, is characteristically normal (DHEAS being the best single test of adrenal maturation). In comparison, both adrenarche and the normal growth spurt are attenuated in CDGP, which is otherwise difficult to distinguish from GnRHdeficiency.

16. Diagnosis When suspected on the basis of the clinical presentation or physical findings, the diagnosis of IHH should be confirmed biochemically. The diagnosis requires the following findings: • The demonstration of prepubertal serum concentrations of sex steroid hormones serum estradiol less than 20 pg/mL in females). • Inappropriately low or normal serum LH and FSH concentrations (usually less than 4 to 5 international units/L) rather than the high concentrations expected with primary gonadal failure. • Otherwise normal anterior pituitary function. • Normal appearance of the hypothalamus and pituitary region on MRI; when seeking this diagnosis, it is useful to request fine (1 mm) cuts through the olfactory bulb region of the MRI to define subtle abnormalities of the olfactory system that may signal which genetic tests to request first.

17. Tumors that affect hypothalamic function (e.g., metastasis, craniopharyngioma) Infiltrative granulomatous disease of the hypothalamus (e.g., sarcoidosis, histiocytosis X, tuberculosis) Pituitary stalk section Pituitary tumors Prolactinoma Clinically nonfunctioning adenoma GH-secreting adenoma (acromegaly) ACTH-secreting adenoma (Cushing disease) Other pituitary tumors (e.g., metastasis, meningioma) Hemorrhagic pituitary destruction, including pituitary apoplexy and Sheehan syndrome Pituitary aneurysm Infiltrative disease of the pituitary (e.g., lymphocytic hypophysitis, sarcoidosis, histiocytosis X, tuberculosis) Empty sellasyndrome Head trauma, Irradiation to the head CNS infection

18. Craniopharyngioma • is a rare embryonic malformation of nonglialorigin (from embryonic squamous remnants of Rathke’spouch) in childhood, a common CNS neoplasm. • This parasellar tumor constitutes about 3% of all intracranial tumors and up to 10% of childhood brain tumors. • Symptoms usually arise before the age of 20 years with a peak incidence between the ages of 6 and 14 years. • 50% have cytogenetic abnormalities. • Symptoms of craniopharyngioma include headache, visual disturbances, optic atrophy or papilledema, short stature, diabetes insipidus, vomiting, signs of GH deficiency, delayed puberty, hypothyroidism and weakness of one or more limbs are features of craniopharyngiomas. • Deficiencies of gonadotropins, GH, thyrotropin, ACTH, and AVP are common and prolactin is normal or increased. • A Rathke cleft cyst is often discovered as an incidental finding on MRI, but it can produce symptoms and signs indistinguishable from those of a craniopharyngioma, such as precocious or delayed puberty.

19. Langerhans Cell Histiocytosis. • Langerhans cell histiocytosisor histiocytosisX is a clonal proliferative disorder of Langerhans histiocytes or their precursors. It is characterized by the infiltration of lipid-laden histiocytic cells or foam cells in skin, viscera, and bone. • Diabetes insipidus, caused by infiltration of the hypothalamus or the pituitary stalk, is the most common endocrine manifestation, with GH deficiency and delayed puberty possible. • The lung, liver, and spleen, cystlike areas in flat and long bones, and the dorsolumbar spine may be involved and exophthalmos due to infiltration of the orbit are seen. • Mastoid or temporal bone involvement may lead to chronic otitis media. Irradiation • Within 10 years after pituitary irradiation, up to 80% of patients may have gonadotroph, somatotroph, thyrotroph, or corticotroph deficits. The mechanism for hypopituitarism appears to involve damage to hypothalamic hormone–releasing cells as well as direct pituitary damage. • Although GH deficiency is the most common hormone disorder resulting from irradiation, gonadotropin deficiency, hypothyroidism, and decreased bone density also occur

20. Empty Sella Syndrome • Damage to the sellar diaphragm may lead to arachnoid herniation into the sellar space. • An empty sella may develop as a consequence of a primary congenital weakness of the diaphragm in those patients in whom no secondary cause is evident. • A secondary empty sella may develop subsequent to infarction of a pituitary adenoma, or surgical or radiation induced damage to the sellar diaphragm. • These patients usually exhibit demonstrable pituitary tissue compressed against the sellar floor, with lateral stalk deviation visible on MRI. • if more than 90% of pituitary tissue is compressed or atrophied, pituitary failure usually occurs. • About 10% of patients may develop small GH- or PRL-secreting adenomas within the narrow rim of compressed pituitary tissue.

21. Sheehan syndrome classically described after severe postpartum hemorrhage . The presentation varies from development of hypovolemic shock resulting in adenohypophyseal vessel vasospasm and pituitary necrosis to the gradual onset of partial to complete pituitary insufficiency over months to years. Initial presentations also include hyponatremia, asthenia, and weight loss. Most prominent among symptoms are inability to nurse and postpartum amenorrhea. Pituitary Apoplexy may result from spontaneous hemorrhage into a pituitary adenoma (pituitary tumor apoplexy) or may occur after head trauma, with skull base fracture, or in association with hypertension and diabetes mellitus, sickle cell anemia, or acute hypovolemic shock. Precipitating factors include major surgery, pregnancy, gamma knife irradiation, anticoagulant therapy, coagulopathy secondary to liver failure and administration of TRH, GnRH agonists, bromocriptine, and cabergoline.

22. Lymphocytic Hypophysitis • This apparently autoimmune inflammatory disorder occurs during or shortly after parturition • It is characterized by a lymphocytic and plasma cell pituitary infiltrate, which may be isolated or associated with other recognized endocrinopathies. • Pathologic criteria for diagnosis include islands of anterior pituitary cells surrounded by diffuse lymphocytic (T and B cell) infiltrates • Over half the patients with lymphocytic hypophysitis present with headache, visual field impairment, and hyperprolactinemia, and pituitary deficiency accounts for the remaining cases • The differential diagnosis includes prolactinoma and other sellar masses, and careful history and demonstrated loss of the posterior pituitary “bright spot” on MRI are useful for supporting the diagnosis. • Laboratory Findings : erythrocyte sedimentation rate is often elevated.

25. Tumors • Functional effect on GnRH pulse (glucocorticoid or prolactin producing tumor), • Anatomical hypothalamus(Langerhans Cell Histiocytosis) stalk (pressure effect, disrupte integrity or increase prolactin) Intrasellar lesion (acromegaly or Non functional adenoma)

26. Thanks for your attention 