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Overview Of Reproductive Steroids Dr. Dave Johnson Dept. Physiology UNECOM.

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1 Overview Of Reproductive Steroids Dr. Dave Johnson Dept. Physiology UNECOM

2 Classes of Steroids Cortical Steroids : Cortisol (C21) Aldosterone (C21) Gonadal Steroids : Progestens or pregnanes (C21) Androgens or androstanes (C19) Estrogens or estranes (C18)

3 Steroid Synthesis Steroids can be synthesized completely from acetate, or directly from the cholesterol molecule. All of the enzymes required by one cell for synthesis of a specific steroid are usually contained within that cell in a "biosynthetic package.

4 Cholesterol Synthesis Inhibition Hydroxy-3-methylglutaryl- CoA (HMGCoA) is reduced by HMGCoA reductase to mevalonic acid in this process. Cholesterol itself feeds back negatively on HMGCoA reductase to inhibit further cholesterol synthesis. Statin drugs (HMGCoA reductase inhibitors) work essentially by mimicking the action of cholesterol on HMGCoA reductase. HMGCoA HMGCoA Reductase

5 The Mother of All Steroids The initial production of all C18, C19, and C21 steroids involves cleaving off the terminal 6 carbons of the cholesterol molecule in the cell mitochondria, to form the steroid pregnenolone. The enzyme responsible for this intial cleaving of the cholesterol side chain is mitochondrial cytochrome P450scc, also referred to as desmolase (cholesterol) (pregnenolone)

6 Steroidogenic Pathways

7 Which Tissues Make Steroids? The primary steroidogenic tissues are the male and female gonads, and the adrenal cortex. Small amounts of in situ steroid synthesis is also now known to occur in the brain, as well as the skin, due to the finding of cytochrome P450scc in these cells. In a patient with a clinical problem associated with too much or too little of some type of steroid, it is important to distinguish between changes in primary synthesis, and changes in peripheral conversion of one steroid to another.


9 Brief Embryology Review Normally, genetic sex or genotype is established at the moment of fertilization. The genetic sex is determined by the haploid sperm cell which fertilizes the haploid oocyte - if this sperm cell contains a Y sex chromosome, the resulting zygote will have an XY pair of sex chromosomes, and will ultimately develop into a male embryo. If the fertilizing sperm cell contains an X sex chromosome, the resulting zygote will have an XX pair of sex chromosomes and the sex of the zygote will be female.

10 Gonad Differentiation In Utero Genotypic sex translates into the appropriate gonadal sex. Normal males and females derive their gonads - the testes and ovaries respectively - from the same embryological tissue…the urogenital ridge. If the developing embryo is a normal genetic male with a single Y sex chromosome, the SRY (sex determining region) gene on the Y chromosome will express gene products around the 7th week of gestation, which will cause the urogenital ridge to begin to evolve into paired testes. In the absence of a Y chromosome (as in a normal, XX genetic female), the urogenital ridge will not be exposed to SRY gene products, and the urogenital ridge will develop into a pair of ovaries beginning around week 11 of gestation.

11 Differentiation of the Urogenital Duct System In Utero Normal genetic males and females both have two genital duct systems prior to secretion of various hormones from the embryonic gonads - the Wolffian ducts, and the Mullerian ducts. Which duct system develops is contingent on the presence or absence of fetal testicles. When present, the Sertoli cells of the testes produce Mullerian-Inhibiting Substance (MIS), which causes the degeneration of the Mullerian duct system. At about the same time MIS is causing regression of the Mullerian duct system in the genetically normal male fetus, testosterone produced from the Leydig cells in the testes causes the Wolffian ducts to differentiate into the seminal vessicles, epididymis, vas deferens, and ejaculatory duct.

12 Differentiation of the External Genitalia A genital tubercle, urogenital groove and labioscrotal folds are present in the fetus by 7 weeks. If the conceptus is male and testes are present, the testes will secrete androgens and cause the urogenital groove to fuse in the midline and become the scrotum, and the genital tubercle will develop into a penis. If the conceptus is genetically female and ovaries are present, there will be little androgen present, and these structures will become the clitoris, urethra, vagina, and labia. So, not only are testicular androgens in adequate amounts required in utero to produce the male phenotype and male duct system in the fetus, but the converstion of androgens in these fetal reproductive tissues to the most potent androgen - 5 alpha dihydrotestosterone - is also required for this process to occur effectively.

13 Abnormalities in Steroidogenic Pathways: CAH The term congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive disorders, each of which involves a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both. Two copies of an abnormal gene are required for disease to occur, and not all mutations and partial deletions result in disease The phenotype can vary from a mild form of disease that is expressed in adolescence or adulthood (NONCLASSIC adrenal hyperplasia) to severe disease that results in adrenal insufficiency at birth with or without virilization and salt wasting (CLASSIC adrenal hyperplasia). 21 alpha hydroxylase

14 Abnormalities in Steroidogenic Pathways: CAH CYP21A is the gene that codes for 21- alpha hydroxylase. Many of the enzymes involved in cortisol and aldosterone synthesis are cytochrome P450 (CYP) proteins. The most common form of CAH is due to mutations or deletions of CYP21A, resulting in 21-alpha hydroxylase deficiency. This deficiency accounts for more than 90% of CAH cases. Mutations or partial deletions that affect CYP21A are common, with estimated frequencies as high as 1 in 3 individuals in selected populations (eg, Ashkenazi Jews) to 1 in 7 individuals in New York City. 21 alpha hydroxylase

15 Presentation of CAH in Genetically Normal Females Females with severe forms of classical CAH due to deficiencies of 21-alpha hydroxylase have ambiguous genitalia at birth due to excess adrenal androgen production in utero. This is often called classic virilizing adrenal hyperplasia. Mild forms of 21- alpha hydroxylase deficiency in females are identified later in childhood because of precocious pubic hair, clitoromegaly, or both, often accompanied by accelerated growth and skeletal maturation due to excess postnatal exposure to adrenal androgens. This is called simple virilizing adrenal hyperplasia. Still miilder deficiencies of 21-alpha hydroxylase activity may present in adolescence or adulthood with oligomenorrhea, hirsutism, and/or infertility. This is termed nonclassic adrenal hyperplasia. 21 alpha hydroxylase

16 Presentation of CAH in Genetically Normal Females TOP: A female patient with the 46,XX karyotype with significant virilization due to 21-alpha hydroxylase deficiency. This patient has clitoromegaly and fusion of the labial-scrotal folds and had salt wasting (due to high androgen and low aldosterone plasma levels). BOTTOM: Severe virilization in a female patient with the 46,XX karyotype with congenital adrenal hyperplasia secondary to 21-alpha hydroxylase deficiency. This patient also had salt wasting.

17 Presentation of CAH in Genetically Normal Males 21- alpha hydroxylase deficiency in males is generally not identified in the neonatal period because the genitalia are normal. If the defect is severe (Classic CAH) and results in salt wasting, these male neonates present at age 1-4 weeks with failure to thrive, recurrent vomiting, dehydration, hyponatremia, hyperkalemia, and shock to due severe volume depletion. Males with less severe deficiencies of 21- alpha hydroxylase present later in childhood because of the early development of pubic hair, phallic enlargement, or both, accompanied by accelerated linear growth and advancement of skeletal maturation.

18 Screening for CAH Screening includes looking for cortisol / aldosterone DEFICIENCIES, and ELEVATED progesterone and 17 alpha- hydroxyprogesterone levels in the plasma. Deficiencies of enzyme activity involved in cortisol synthesis result in elevations in concentrations of adrenocorticotropic hormone [ACTH] that often cause hyperpigmentation. This hyperpigmentation may be subtle and is best observed in the genitalia and areolae. Hyponatremia with hyperkalemia in a newborn male or female should always raise the possibility of a severe form of CAH!! 21 alpha hydroxylase

19 Treatment of CAH All patients who have classic CAH due to 21- alpha hydroxylase deficiency receive long- term glucocorticoid or aldosterone replacement (or both), depending on whether cortisol and/or aldosterone synthesis is affected. Another approach currently under investigation is the combined use of a glucocorticoid and/or mineralocorticoid, along with an aromatase inhibitor (to slow skeletal maturation), and flutamide or bicalutamide (androgen receptor antagonists, to reduce virilization). Some patients develop precocious puberty, which further compromises adult height. Suppression of puberty with long-acting gonadotropin-releasing hormone (GnRH) agonists while simultaneously stimulating growth with growth hormone treatment may partially improve the patient's height. The traditional approach to the female patient with ambiguous genitalia at birth due to classical CAH is clitoral recession early in life followed by vaginoplasty after puberty.

20 Total Plasma Steroid Levels in Adults Plasma steroids are maintained at levels much lower than plasma cholesterol levels (cholesterold levels are approximately 1.5 million ng/ml, equivalent to about 150 mg/dl). Only those cells with steroid hormone receptors will take up and accumulate circulating steroids. Only steroid that is unbound to plasma proteins (ie, free steroid can be taken up and bind to steroid receptor in tissues that utilize steroids (this is typically less than 2% of the total plasma steroid concentration)

21 Plasma Steroid Binding Although albumin binds to all steroids, its binding affinity for steroids is weak. Sex steroid binding globulin (also called sex hormone binding globulin or SHBG) has HIGH affinity for androgens and estrogens, but low affinity for progestagens and cortisol.

22 Plasma Steroid Binding Since the albumin-bound fraction of steroids rapidly dissociates and the free steroid can then be taken up by target tissues, circulating BIOACTIVE steroid is the sum of the "albumin-bound" plus the "free " steroid.

23 Assessing Androgen Status In a patient with symptoms of excess androgenism (such as a female who develops hirsutism and acne), simply looking at total plasma androgens is not sufficient to find if excess androgenism is the problem. However, examining the plasma levels of SHBG is very useful in these instances.

24 Assessing Androgen Status The free Androgen Index (FAI) provides a convenient assessment of bioavailable testosterone. It is calculated as the ratio of total serum testosterone divided by SHBG; FAI = Total Testosterone (nmol/L) X 100 SHBG(nmol/L)

25 Steroid Receptors Steroid hormone receptors are intracellular (found in both the cytoplasm and nucleus) receptors that perform signal transduction for steroid hormones. Steroid receptors are part of the nuclear receptor family that includes receptors that bind to non-steroid ligands such as thyroid hormones and vitamins A and D. When these receptors bind ligands, they undergo a conformational change that renders them activated to recognize and bind to specific nucleotide sequences in the DNA known as hormone-response elements (HREs). Protein transcription follows

26 Androgen Insensitivity Syndrome (formerly Testiclular Feminization) Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in male individuals with a normal 46,XY karyotype. AIS represents a spectrum of defects in androgen action due to MUTATIONS IN THE ANDROGEN RECEPTOR GENE and can be subdivided into three broad gonadal phenotypes at birth: 1.Complete androgen insensitivity syndrome (CAIS), born with normal appearing female genitalia. 2.Partial androgen insensitivity syndrome (PAIS) born with ambiguous genitalia. 3Mild androgen insensitivity syndrome (MAIS) with normal appearing male genitalia.

27 Androgen Receptor Dysfunction in AIS The gene for the human androgen receptor is located within the Xq area of the X chromosome. There are over 200 known mutations. Incidence of complete AIS is about in 1 in 20,000. Milder forms may be more common than CAIS (unknown). Evidence suggests many cases of unexplained male infertility may be due to the mildest forms of AIS.

28 Complete Androgen Insensitivity Syndrome The basic etiology of CAIS is a COMPLETE loss-of-function mutation in the androgen receptor gene in XY males. Individuals with CAIS are born with female external genitalia with normal labia, clitoris, and a vaginal opening. Affected individuals have normal testes (usually located abdominally) with normal production of testosterone and normal conversion to dihydrotestosterone (DHT), which differentiates this condition from 5- alpha reductase deficiency. Because the testes produce normal amounts of müllerian-inhibiting factor (MIF), also known as müllerian-inhibiting substance (MIS), affected individuals do not have fallopian tubes, a uterus, or a proximal (upper) vagina.

29 Complete Androgen Insensitivity Syndrome All patients with AIS are chromosomally and gonadally normal males. However, separating the concepts of sex and gender is crucial with these patients. The term sex usually is based on physical attributes, while the concept of gender is based on an individual's self-concept and self-identification as well as the role an individual assumes in society. Most patients with CAIS assume a female gender when diagnosed (usually in their early teens, when failure to menstruate results in a clinical work-up). The significance of the lack of androgen effect during development is increasingly recognized for its influence on the maturing brain in terms of developing adult gender identity.

30 AIS Patient This is actually an XY male with CAIS. The lack of androgen receptors in this individual means that, despite exposure to adequate levels of androgens (from abdominal testes) both in utero and at puberty, the female phenotype differentiated as there was no androgen binding. Because high levels of androgens at puberty were not taken up by tissues with androgen receptors, the androgens were aromatized to estrogens in other tissues, including breast tissue.

31 Inheritance Mode of AIS AIS is inherited in an X-linked recessive pattern. A condition is considered X- linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In genetic males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In genetic females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. About two-thirds of all cases of AIS are inherited from mothers who carry an altered copy of the AR gene on one of their two X chromosomes. The remaining cases result from a new mutation that can occur in the mother's egg cell before the child is conceived or during early fetal development.

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