Reproduction-Related Disorders Part 2

Hypothalamic -Pituitary-Gonadal Axis In adult women, a tightly coordinated feedback system exists between: (1) hypothalamus, (2) anterior pituitary, and (3) ovaries to organize menstruation. FSH serves to stimulate follicular growth, and LH stimulates ovulation and progesterone secretion from the developing corpus luteum.

Hypothalamic -Pituitary-Gonadal Axis Estrogens Estrogens are responsible for the development and maintenance of female sex organs and female secondary sex characteristics. In conjunction with progesterone, they participate in: Regulation of the menstrual cycle, Breast and uterine growth, and The maintenance of pregnancy Estrogens affect calcium homeostasis and have a beneficial effect on bone mass.

Hypothalamic -Pituitary-Gonadal Axis Estrogens Estrogens also increase concentrations of plasma proteins including: Sex hormone binding globulin (SHBG), Corticosteroid binding globulin, and Thyroxine-binding globulin. Concentrations of plasma proteins that bind copper and iron are also elevated in response to estrogen, as are the concentrations of high-density lipoproteins.

Hypothalamic -Pituitary-Gonadal Axis Progesterone This hormone is especially important in preparing the uterus for implantation of the blastocyst and in maintaining pregnancy. In nonpregnant women, progesterone is secreted mainly by the corpus luteum. During pregnancy, the placenta becomes the major source of this hormone. Minor sources are the adrenal cortex in both sexes and the testes in men.

Female Reproductive Abnormalities A wide variety of abnormalities affect the female reproductive system. They have been divided into categories of: Pseudohermaphroditism, Precocious puberty, Irregular menses, and Menopause.

Female Reproductive Abnormalities 1- Female Pseudohermaphroditism The female pseudohermaphrodite is an individual who is genetically female, but whose phenotypic characteristics are, to varying degrees, male. In neonates with a 46,XX karyotype and ambiguous genitalia, congenital adrenal hyperplasia (CAH) should be considered. CAH is a family of autosomal recessive disorders of adrenal steroidogenesis. Each disorder has a specific pattern of hormonal abnormalities resulting in deficiency or excess of androgens. Only deficiencies of 21-hydroxylase and 11β-hydroxylase enzymes are predominantly virilizing disorders. Overproduction of androgens leading to masculinization of external genitalia in females and early virilization in males

Female Reproductive Abnormalities 1- Female Pseudohermaphroditism Diagnosis of 21-hydroxylase deficiency is made in infants and children with excess excretion of urinary 17-ketosteroids (17-KS) and pregnanetriol and elevated concentrations of plasma 17- hydroxyprogesterone and androstenedione. Elevation of 17-hydroxyprogesterone concentrations in early infancy (>3000 ng/dL) confirms the diagnosis of this disorder. 17-KSs are metabolites o precursors secreted by the (1) adrenal glands,

Female Reproductive Abnormalities 1- Female Pseudohermaphroditism An 11β-hydroxylase deficiency is confirmed by finding: Elevated plasma concentrations of 11–deoxycortisol and deoxycorticosterone, Increased concentrations of their metabolites in urine, and their suppression by glucocorticoid therapy. Plasma aldosterone concentrations is low in this deficiency

Female Reproductive Abnormalities 2- Precocious Puberty The development of secondary sexual characteristics in girls younger than 8 years old and boys younger than 9 years old. Early puberty is manifested by the appearance of secondary sexual characteristics, such as: Premature thelarche (premature breast development), Premature adrenarche (premature sexual hair development), or Phallic enlargement.

Female Reproductive Abnormalities 2- Precocious Puberty When presented as isolated cases, these secondary sexual characteristics are not considered to be pathologic, as none progresses to full-blown puberty, nor are they associated with increased rates of bone growth and maturation. However, if a child has at least two signs of puberty and also demonstrates increased rates of bone growth and maturation, the many causes of true precocious puberty must be considered.

Female Reproductive Abnormalities 2- Precocious Puberty Precocious puberty has been classified as GnRH dependent or independent. GnRH-dependent precocious puberty (also called central precocious puberty) is due to precocious activation of the hypothalamic-pituitary-gonadal axis. Pseudoprecocious puberty (also called GnRH-independent precocious puberty) refers to precocious sex steroid secretion that is independent of pituitary gonadotropin release. CAHs are a common cause of pseudoprecocious puberty. Other causes include tumors of the (1) adrenal gland, (2) ovaries, and (3) testes that secrete androgens or estrogens.

Female Reproductive Abnormalities 2- Precocious Puberty laboratory tests performed to assess gonadotropin concentrations and response to exogenous GnRH. The GnRH stimulation test is the gold standard for diagnosis of GnRH-dependent precocious puberty. Pubertal responses of LH and FSH to GnRH stimulation are considered diagnostic of precocious puberty when chronological age is inappropriate for the hormone response. The GnRH stimulation test is also used to monitor the effectiveness of GnRH agonist therapy. Typically, an IV administration of exogenous GnRH is administered followed by a single measurement (at 40 to 45 minutes) or serial measurements of LH and FSH concentrations.

Female Reproductive Abnormalities 3- Irregular Menses Healthy women display considerable variation in cycle length ranging from 25 to 30 days (28 days on average). Amenorrhea, the absence of menstrual bleeding, is traditionally categorized as: Primary (women who have never menstruated) or Secondary (women in whom menstruation is present for a variable time and then ceases). Amenorrhea is a relatively common disorder with an estimated prevalence of 5%

Female Reproductive Abnormalities 3- Irregular Menses/ Primary Amenorrhea Primary amenorrhea is defined as failure to establish natural periodic menstruation by the age of 16 years regardless of whether secondary sex characteristics have developed. About 40% of phenotypic females who have primary amenorrhea have Turner syndrome (45,X karyotype) or pure gonadal dysgenesis (46,XX or XY karyotype) nearly always associated with absence of development of secondary sex characteristics Müllerian duct agenesis or dysgenesis with absence of the vagina or uterus is the second most common manifestation, The third most common is AIS (AR deficiency) and normal or elevated plasma testosterone concentrations if the patient is past puberty and is karyotype XY. Müllerian agenesis is a congenital malformation characterized by a failure of the Müllerian duct to develop, resulting in a missing uterus androgen insensitivity syndrome

Low concentrations may indicate pituitary failure. Female Reproductive Abnormalities 3- Irregular Menses/ Primary Amenorrhea When puberty is delayed in a girl, plasma concentrations of serum gonadotropins are measured. Low concentrations may indicate pituitary failure. Pituitary function testing and radiography may be helpful. Patients with short stature without Turner syndrome but with primary amenorrhea may have multiple deficiencies of pituitary hormone secretion. In these patients, a craniopharyngioma or pituitary tumor should be suspected. Craniopharyngioma is a type of brain tumor 

Differential Diagnosis of Amenorrhea

Female Reproductive Abnormalities 3- Irregular Menses/ Secondary Amenorrhea Secondary amenorrhea is defined as absence of periodic menstruation for at least 6 months in women who have previously experienced menses. With few exceptions, the causes of primary and secondary amenorrhea overlap. Pregnancy, the most common cause of secondary amenorrhea, must be considered first and ruled out. Elevated concentrations of prolactin—iatrogenic or induced by a prolactin secreting tumor—can result in oligomenorrhea or amenorrhea. Oligomenorrhea is infrequent menstruation that occurs fewer than nine times per year. Oligomenorrhea is infrequent menstruation that occurs fewer than nine times per year.

Female Reproductive Abnormalities 3- Irregular Menses/ Secondary Amenorrhea It is thought that hyperprolactinemia inhibits the release of LH and FSH. Both hyperthyroidism and hypothyroidism are associated with a variety of menstrual disorders because of their effects on metabolism and inter- conversion of androgens and estrogens.

Serum or urine hCG should be measured to rule out pregnancy. Female Reproductive Abnormalities 3- Irregular Menses/ Secondary Amenorrhea Serum or urine hCG should be measured to rule out pregnancy. Because both hypothyroidism and hyperprolactinemia have been known to cause amenorrhea, they are easily excluded by measuring concentrations of serum TSH and prolactin. A 24-hour urine cortisol or an overnight dexamethasone suppression test is performed in those patients suspected of having Cushing syndrome. A GnRH stimulation test with measurement of LH and FSH concentrations in those patients with gonadotropin deficiency assists in differentiating hypothalamic disease from pituitary disease. The low-dose test can help tell whether your body is producing too much ACTH. The high-dose test can help determine whether the problem is in the pituitary gland (Cushing disease). corticotropin-releasing hormone (CRH). Adrenocorticotropic hormone (ACTH)

Female Reproductive Abnormalities 4- Menopause Menopause begins with the ovaries failing to produce adequate amounts of estrogen and inhibin; as a result, gonadotropin production is increased in a continued attempt to stimulate the ovary. The mean age of menopause in the United States is 51 years but varies considerably. Ovarian failure may occur at any age, but menopause before age 40 years is considered premature. Hormonal changes begin about 5 years before the actual menopause, as the response of the ovary to gonadotropins begins to decrease and menstrual cycles become increasingly irregular.

Female Reproductive Abnormalities 4- Menopause The term perimenopausal refers to the time interval from onset of these menstrual irregularities to menopause itself. This transition phase will last rom 2 to 8 years. At this time, FSH concentrations increase and E2 concentrations decrease, whereas LH and progesterone concentrations remain unchanged. The decrease in estrogen concentrations gives rise to vasomotor instability and “hot flashes.

Female Reproductive Abnormalities 4- Menopause After menopause, the ovary continues to produce androgens, particularly testosterone and androstenedione, as a result of increased LH concentrations. In addition, the adrenal gland continues to secrete androgens. The resulting decrease in the estrogen/androgen ratio causes the hirsutism often seen in postmenopausal women. Prolonged estrogen deficiency results in increased resorption and bone remodeling, leading to accelerated bone loss and osteoporosis in postmenopausal women.

Female Reproductive Abnormalities 4- Menopause It is important to note that perimenopausal and postmenopausal women secrete pituitary hCG. Serum concentrations generally are low (<13 IU/L), but positive hCG results often causes confusion and delays important diagnostic tests or treatments. Pituitary versus placental hCG has been confirmed by measuring serum FSH (concentrations of FSH >45 IU/L are consistent with menopause and make pregnancy unlikely) or by 2 weeks of hormone replacement therapy (hormone replacement therapy should decrease LH, FSH, and hCG concentrations).