FEMALE REPRODUCTIVE ENDOCRINOLOGY MBBS.pptx

Chemical pathology, female reproductive pathology, laboratory medicine

1. FEMALE REPRODUCTIVE ENDOCRINOLOGY Dr Aisha S.K

2. NORMAL PHYSIOLOGY Normal reproductive function is mediated by a variety of hormones synthesized and secreted by the gonads (testes and ovaries), adrenals, pituitary, hypothalamus , and placenta In addition, peripheral non glandular tissues can contribute to hormone synthesis

3. Biosynthesis of estrogen The three most biologically active estrogens are estrone (E1), estradiol (E2), and estriol (E3) Estrogens are secreted by the ovarian follicles and the corpus luteum , and during pregnancy by the placenta Synthesis of estrogens begins in the theca interna cells with the enzymatic synthesis of androstenedione (androgen) from cholesterol

4. Ovarian hormones Androgens (C19 steroids), synthesized by theca cells of the ovary and are converted into oestrogens (C18 steroids) in the granulosa cells The liver and subcutaneous fat convert ovarian and adrenal androgens to oestrogens

5. Cont’d sex steroids become reversibly and non covalently bound to plasma proteins Sex hormone–binding globulin (SHBG) transports androgens and estrogens, and corticosteroid binding globulin (CBG) transports progesterone (as well as glucocorticoids ) In blood, only about 1% to 2% of the sex steroids are free (unbound ) and biologically active About half of the remainder are bound to SHBG or CBG, and about half are bound to albumin

6. Regulation of female reproduction GnRH from the hypothalamus increases the synthesis and secretion of FSH and LH from the anterior pituitary. Unlike in the male, however, the regulatory process in the female is cyclic and is referred to as the menstrual cycle Pituitary, ovarian, and uterine changes that occur during the menstrual cycle ; the cycle begins with menses, or shedding of uterine endometrium, which is considered day one. During this period in the ovary, a cohort of follicles is recruited to begin further growth and development From this cohort, one to two (usually) is selected to be the dominant follicle and to continue to grow and develop. The other recruited follicles undergo regression, or atresia

7. Cont’d These processes occur during the follicular phase of the ovarian cycle, primarily as a result of the action of FSH As the follicle grows, increasing amounts of estradiol are synthesized and secreted from them Estradiol restores the endometrium via cell proliferation and growth—hence the proliferative phase of the uterine endometrial cycle. Estradiol also has a negative-feedback effect on the hypothalamus and the anterior pituitary, causing a decline in FSH levels during the latter part of the follicular phase.

8. Cont’d Near the end of the follicular phase, when estradiol levels are at their highest , its feedback effect on the hypothalamus and anterior pituitary switches to positive . The exact mechanism for this change to positive feedback is not understood Its effect, however, is dramatic It causes a surge in the secretion of LH, which culminates in ovulation The LH surge causes final oocyte maturation with the completion of meiosis. The oocyte enters the oviduct. Owing to disruption of the follicle, estradiol synthesis and secretion drop dramatically. The

9. Laboratory evaluation of reproductive function laboratory findings in various male and female reproductive disease states typically categorized according to ( 1) hormone deficiency or excess and (2) primary (gonad) or secondary ( pituitary) dysfunction. In primary disease states, gonadal steroid levels are inversely related to pituitary gonadotropin levels, whereas in secondary disease states , they are directly related (e.g., both high or both low )

10. Con’t These changes occur because gonadal steroids provide negative feedback to gonadotropins For example, in primary ovarian failure or menopause, the decrease in estradiol reduces its negative-feedback effect on the hypothalamic pituitary axis , resulting in increases in FSH and LH.

11. Female evaluation Evaluation of the female reproductive system can be simplified to confirmation of ovulation and normal female reproductive anatomy The abnormal menstrual cycle pattern is one of the best predictors of anovulation Amenorrhea can be defined as the absence of menstrual flow by age 16, or by age 14 if no breast development occurs

12. Primary Amenorrhea Primary amenorrhea is defined as failure to establish spontaneous periodic menstruation by the age of 16 years regardless of whether secondary sex characteristics have developed Müllerian duct agenesis or dysgenesis with absence of the vagina or uterus is the second most common manifestation, and the third most common is androgen insensitivity syndrome (androgen receptor deficiency and normal or elevated plasma testosterone concentrations if person is karyotype XY

13. Secondary Amenorrhea Secondary amenorrhea is defined as absence of periodic menstruation for at least 6 months in women who have previously experienced menstration pregnancy is the most common cause of secondary amenorrhea Elevated concentrations of prolactin —iatrogenic or induced by a prolactin -secreting tumor—have been found to result in oligomenorrhea [ Oligomenorrhea is infrequent menstruation that occurs fewer than nine times per year] or amenorrhea About one third of women with no obvious cause of amenorrhea have elevated prolactin concentrations

14. Another rare cause of amenorrhea is the so called resistant ovary syndrome,this condition is associated with increased concentrations of plasma FSH and LH, and ovaries that contain predominantly primordial follicles

15. Cont’d In patients who have not exhibited menses by age 16, this is often due to a genetic and/or anatomic abnormality In such cases, however, an endocrine abnormality is still a possible cause, and the presence or absence of secondary sexual characteristics (e.g., breast development ) is an important indicator in the evaluation An endocrine abnormality is a more likely cause in patients who have a history of menstruation but have not experienced menses for more than 3 months. A stepwise approach to evaluating amenorrhea is based on measuring hCG , PRL, TSH, free thyroxine (FT4), FSH, LH, and androgen levels and assessing estrogen status.

16. Cont’d Step 1: CG is measured to exclude pregnancy Although a result of greater than 5 mIU /mL is typically indicative of pregnancy, an elevated result can also be obtained with trophoblastic disease or an hCG -secreting tumor Step 2: PRL, TSH, and FT4 are measured to exclude the endocrine disorders. Increased prolactin accompanied by normal TSH and FT4 results suggests a prolactinoma , which would be further evaluated by imaging techniques Hyperprolactinemia , however, can also be caused by primary hypothyroidism , as indicated by high TSH and low FT4 Low TSH and FT4 suggest secondary hypothyroidism, in which case the patient should be evaluated for panhypopituitarism , a deficiency of all anterior pituitary hormones Hyperthyroidism (increased FT4) can also be associated with amenorrhea.

17. Cont’d Step 3: If hCG , PRL, TSH, and FT4 are all normal, then endogenous estrogen status is evaluated with the progestin withdrawal test. Progestin may be administered orally for 5 to 10 days or in one intramuscular injection (progestin dissolved in oil). The presence of withdrawal bleeding within 7 days after treatment indicates ( 1) that the outflow tract is intact and ( 2) that sufficient estrogen was present at the outset to stimulate endometrial growth If withdrawal bleeding is absent, the genital tract should be evaluated using imaging techniques.

18. Cont’d Step 4 : Serum FSH and LH levels should be determined. Elevated FSH and LH indicate primary ovarian failure, whereas low or inappropriately normal FSH and LH indicate secondary ovarian failure The latter is of hypothalamic-pituitary origin and can result from a variety of clinical disorders, including Sheehan’s syndrome, eating disorders, weight loss, and stress If withdrawal bleeding is present, then Step 5 is followed.

19. Cont’d Step 5 : Androgen excess should be evaluated. Elevated testosterone (> 150 ng /mL) indicates a tumor or polycystic ovarian syndrome The latter is a clinical entity often associated with enlarged ovaries and infertility , as well as amenorrhea. Increased DHEAS suggests an adrenal tumor. 17-OH progesterone is an androgen precursor , and an increase in serum levels can indicate congenital or adult onset adrenal hyperplasia due to 21-hydroxylase deficiency These abnormalities may be accompanied by hirsutism (i.e., male pattern of hair growth in females ) The tests in Step 5 can also be used to evaluate hirsutism when it is the primary clinical presentation

20. Cont,d Because amenorrhea or oligomenorrhea is often associated with infertility Evaluation of the ovulatory function is an important step in the infertility workup One of the methods used to confirm ovulation is monitoring the basal body temperature. A rise in progesterone after ovulation increases basal body temperature by 0.4° F to 0.8° F, but it is not as reliable or used as often More reliable are urinary ovulation predictor kits , which measure urinary luteinizing hormone

21. Infertility Infertility can be defined as primary when conception has never occurred despite at least 1 year of unprotected coitus , and secondary when there has been a previous pregnancy , either successful or not Investigation earlier than 1 year may be appropriate if the woman is more than 35 years old or where pregnancy is associated with other risks In cases of infertility, both partners should be investigated The history should include coital frequency and success, serious illnesses, use of alcohol and drugs, and sexually transmitted diseases.

22. Cont’d Female Examination should include looking for anorexia nervosa , hirsutism , virilism , galactorrhoea and ambiguous genitalia A history should also be taken for medications and drugs

23. Investigations A woman may be infertile despite having a clinically normal menstrual cycle (about 95 per cent of such cycles are ovulatory ) Thus , even if the cycle seems to be regular , it is important to determine whether ovulation is occurring and if luteal development is normal Anovulatory infertility is probably the most common form of female infertility and is associated with oligomenorrhoea or amenorrhoea

24. Cont’d If the patient is menstruating regularly, measure plasma progesterone concentration during the luteal phase on day 21 of the cycle A normal plasma concentration is strong evidence that the patient has ovulated A low plasma concentration of < 30 nmol /L suggests either ovulatory failure or impaired luteal function. This investigation should be repeated on more than one occasion The most common cause of a low progesterone concentration (< 30 nmol /L) is inaccurate sample timing, although, if authentic, it suggests lack of ovulation

25. Cont’d Follicular development and ovulation may be monitored by ovarian ultrasound examination. Polycystic ovary syndrome should be excluded Plasma follicle-stimulating hormone (FSH), LH, oestrogen and testosterone concentrations are useful, as is the exclusion of thyroid disease If there is primary amenorrhoea , consider karyotyping the patient, for example Turner’s syndrome (45,XO).

26. Cont’d Do the plasma FSH, LH and oestrogen results suggest hypergonadotrophic hypogonadism or hypogonadotrophic hypogonadism ? In the presence of amenorrhoea , a plasma FSH of more than 40 U/L is suggestive of ovarian failure Low concentrations of plasma gonadotrophins may necessitate a gonadotrophin -releasing hormone ( GnRH ) test to look for pituitary or hypothalamic disease Anti- Müllerian hormone (AMH) is released by granulosa cells of the ovarian follicle and low serum concentrations suggest poor ovarian ‘reserve’ ( the size of the ovarian ovum supply). Serum AMH may , thus, have a place in the investigation of infertility .

27. Ovarian failure When the diagnosis of ovarian failure is suspected, the level of FSH in the early follicular phase (on day 3) should be determined, because, as mentioned earlier, it will be elevated. Concentrations greater than 10 mIU /mL are associated with diminished ovarian reserve Diminished ovarian reserve is associated with decreased probability of live birth

28. Cont.d More extensive testing of ovarian reserve includes the clomiphene citrate challenge test Clomiphene citrate, the nonsteroidal estrogen receptor modulator , is administered on day 5 through day 9 (or days 3 to 7) of the cycle; this is followed by measurements of estradiol and FSH on day 3 and on day 10 Women with a poor cohort and aging follicles cannot generate enough estradiol or inhibin B to suppress FSH Therefore , FSH remains high.

29. CASE 3 A 28-year-old woman attended the gynaecology outpatient clinic because of infertility. Her periods were noted to be irregular. She was on no medication, and her renal function, liver function and blood glucose concentration were normal. Her plasma results were as follows : Thyroid-stimulating hormone 2.1 mU /L (0.20–5.0) Free thyroxine 14.3 pmol /L (12–25) Prolactin 414 mU /L (< 470) Luteinizing hormone 7.2 U/L (1–25) Follicle-stimulating hormone 5.4 U/L (1–15) Testosterone 1.7 nmol /L (1–3) Sex-hormone-binding globulin 33 nmol /L (20–90) Oestradiol 564 pmol /L (70–880) 21-day plasma progesterone 6.6 nmol /L (> 30 suggests ovulation )

30. DISCUSSION The low 21-day plasma progesterone concentration suggests a poor luteal phase and possible anovulation The patient was having anovulatory menstrual cycles, which explained her infertility.

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32. References Tietz textbook of clinical chemistry and molecular diagnosis 5 th edition HENRY’S Clinical Diagnosis and Management by Laboratory Methods 23 rd Edition Clinical Biochemistry & Metabolic Medicine 8 th edition