Gonadal function/disorders

Question 1

Most adrenal biosynthetic defects result in

Answer 1

• Virilized female
●Normally virilized male
●Deficiencies:
●Mineralocorticoid
●Glucocorticoid
●21-OHase deficiency
●11-OHase deficiency

Question 2

How does CYP deficiency manifest in a female

Answer 2

Deficiency of CYP 17
●17α- hydroxylase and 17-20 lyase deficiency
●Rare cause
●Diagnosed due to delayed pubertal development
Female: 46xx:
●Hypertensive
●+/- Hypokalemia
●Primary amenorrhea
●Absent secondary sex characteristics

Question 3

How does CYP 17 manifest in a male

Answer 3

Complete male pseudohermaphroditism
●Female external genitalia
●Blind-ended vagina
●No mullerian structures
●Testes intra-abdominal
●Leydig cell hyperplasia
●Hypertensive
●+/- Hypokalemia
•Cortisol sufficient
●Tolerates general anesthesia and surgery
Treatment
●Steroids to suppress excess ACTH
●Gonadal steroid replacement

Question 4

What is β-Hydroxysteroid Dehydrogenase deficiency

Answer 4

β-Hydroxysteroid Dehydrogenase
●Presents early infancy
●Adrenal insufficiency
●Females can be virilized due to DHEA
●Males:
●Normal genital development
●Hypospadias
●Pseudohermaphroditism
Females:
●Can present in puberty with:
●Hyperandrogenemia
●Hirsuitism
●Oligomenorrhea
●Treatment
●Cortisol replacement

Question 5

What is Steroidogenic Acute Regulatory Protein (StAR) deficiency

Answer 5

StAR Deficiency
●Transports cholesterol to inner mitochondrial membrane
●Rarest form of CAH
●Autosomal recessive
●All adrenal steroids are deficient
●Presents with adrenal insufficiency
●Typically fatal in infancy
Males:
●Female external genitalia

Question 6

What are the sexes as determined by chromosome (males, females, klinefelter and turner’s syndromes)

Answer 6

●Normal male: 46 XY karyotype
●Normal female: 46 XX karyotype
●Klinefelter’s syndrome: 47 XXY,
48 XXXY, 46 XX/XY mosaic ♂
●Turner’s syndrome: 45 XO, ♀
●The sex chromosomes determine whether the primitive gonads become testes or ovaries

Question 7

What are some causes of male and female gonadal disorders

Answer 7

Secondary:
●Genetic (abnormalities of hypothalamus or pituitary)
●Kallmann’s: GnRH def
●GnRH receptor mutations
●Isolated LH or FSH deficiency
●Mutations that lead to absence of some pituitary hormones

Secondary & Tumorous
●Pituitary tumours,PrL
●Various brain tumours: craniopharyngioma, astrocytoma
●Head trauma

Question 8

Mention some facts about Klinefelter’s syndrome

Answer 8

Klinefelter’s syndrome (47 XXY)
● XY gonadal dysgenesis
●LH & FSH receptor mutations
●Testicular infections e.g. mumps
●Chemotherapy and irradiation of gonads

Question 9

Mention some facts about Turner’s syndrome

Answer 9

Turner’s syndrome (45, XO)
●XX gonadal dysgenesis
●LH & FSH receptor mutations
●Autoimmune ovary resistance
●Chemotherapy and irradiation of gonads

Question 10

What are some other causes of male and female gonadal disorders

Answer 10

Chemical or cellular defects in androgen synthesis
●Others : Testicular feminization syndrome which may be due to inactive androgen receptor activities

●Primary ovarian failure (POF)
●Polycystic ovarian syndrome
Miscellaneous
●Amenorrhoea
●Oligomenorrhoea
●Hirsutism ; increase in body hair with male pattern distribution (may be genetic and benign)
●Virilism: Testosterone , clitoromegaly, breast atrophy, deep male voice
●Others: Cushing’s syndrome, Acromegaly

Question 11

What is subfertility

Answer 11

Defined as the failure of a couple to conceive after one year of unprotected intercourse.
●The cause could be either male or female or both
●A full clinical history on the couple e.g. previous pregnancies, use of contraceptives, serious illness, chemotherapy, STDs etc. is required
●♂: Initial semen analysis should be performed i.e. vol., sperm morphology, count, motility etc.
●♀: Needs physical examination by an O&G specialist
●Thorough lab. Investigations in each partner

Question 12

What does male fertility depend on

Answer 12

Depends on production of adequate numbers of healthy spermatozoa and their subsequent delivery to the upper female tract
●Hindered by hypospadias and impotence

Question 13

What are some causes of female infertility

Answer 13

Ovulatory failure:
Total, & infrequent ovulation
(Orderly FSH stimulation followed by a midcycle LH surge  maturation + ovulation of selected Graafian follicle)
●Hyperprolactinaemia inhibits ovulation (normal in pregnancy and lactation)
Failure of ovaries to respond normally to gonadotrophins e.g. in the polycystic ovary (Stein-Leventhal) syndrome (PCOS)
●Oestrogen effects on endometrium and cervical mucus affect fertility
●Tubal blockage: Salpingitis, PID & pelvic peritonitis can damage ciliated epithelium
●Hypothyroidism (a possibility in obese infertile women)
●Diabetes (badly controlled)
●Uterine fibromyomata:
large ones that distort the uterine cavity or block the interstitial parts of the tubes may cause infertility
Endometriosis:
Seen in women who either have never been pregnant or not been pregnant for some years
●Endometriosis causes peritubular adhesions and is associated with dyspareunia leading to infrequent sexual intercourse
●Fixed retroverted uterus (unlikely cause unless associated with salpingitis and endometriosis)

Question 14

What are some history required in the investigation of the infertile couple

Answer 14

♀: Menstrual Hx
●Previous gynaecological Hx
●Hx of pelvic infection
●General state of health and nutrition
●♂: Hx of sexual function, erection and ejaculation
●Hx of orchitis and venereal disease
●Frequency of intercours

Question 15

What are laboratory investigations of subfertility in the male

Answer 15

No endocrine investigation should be done in eugonadal male with normal sperm analysis
●In hypogonadal male, testosterone and gonadotrophins should be investigated
●FSH, LH will be elevated but Testosterone will be decreased in Primary testicular failure
●In hypothalamic –pituitary diseases, there would be low testosterone with low or normal gonadotrophins

Question 16

Explain seminal fluid analysis

Answer 16

●This should normally be the first step in investigation because it is pointless investigating the female if no sperm are present
●Investigation of the female involves a lot of tests, therefore it is better to start with the few tests in the male After 3 days’ abstinence, a specimen of semen is collected in a sterile plastic container after ? masturbation or coitus using sterile sheath (containing no spermicide) and examined within a few hours.
●The figures given are average and considerable variation occurs from individual to individual
●The figures given reflect the man’s state of health 70 days previously, when the spermatozoa were formed
(we would need to confirm this information)
●For a correct evaluation of male fertility, two or three consecutive specimens of semen may need to be examined especially when the first analysis shows any abnormality
●Azoospermia is the term used when there are no spermatozoa in the semen
●Oligospermia is the term applied when there are less than 10 million spermatozoa per millilitre
●Once the seminal fluid analysis has been carried out and found to be normal, the next steps are tests for ovulation and tubal patency

Question 17

What are some laboratory investigations of subfertility in the female

Answer 17

NB. Investigation will depend on which phase of the menstrual cycle the woman is in viz; Ovulatory, follicular, luteal etc.
●LH, FSH, E2, Testo, Prolactin, Pg (profiles will depend on the disorder or cause of subfertility)
●In (primary ovarian failure) POF- there is elevated LH, FSH but low E2

Question 18

How is ovulation tested for

Answer 18

Oral temperature is taken every morning on waking and is recorded on a special temperature chart
●A rise in the basal body temperature of about 0.5ºC in the last 14 days of the cycle indicates that ovulation has taken place
●Examination of the cervical mucus in the mid-cycle will reveal characteristic changes if ovulation has occurred
• Ovulatory mucus is clear and copious, and can be drawn out into a fine thread ‘spinnbarkheit’. On drying it crystallizes out into a fine fern-like pattern
●A sample of blood is taken one week before a period is expected i.e. day 21 of a 28 day cycle. A progesterone level of more than10 ng/ml in this confirms that ovulation has taken place
• Histological examination of premenstrual endometrial biopsy shows secretory changes in the glands after ovulation
●This investigation is commonly combined with laparoscopic examination of the fallopian tubes

Question 19

What are some tests for tubal patency

Answer 19

Laparoscopic method (invasive)
●Premenstrual laparoscopic examination of the tubes combined with injection of a dilute solution of methylene blue through a tightly fitting cannula placed in the cervical cannal is used to investigate tubal patency
●The uterus distends with the dye and if the tubes are patent, they fill with dye which finally spills from the distal ends
●In distal block there is no spill
●In medial block no dye enters the tubes
●Patients are warned not to get pregnant in the cycle in which such an investigation is carried out
• Hysterosalpingography

Question 20

What is hysterosalpingography

Answer 20

Injection of a radio-opaque aqueous iodine solution through the cervix under radiographic control remains a most useful investigation for tubal patency
●This test should be performed during the first 10 days of the cycle after menstrual bleeding has ceased but before ovulation has occurred
●An X-ray image intensifier and a television screen are employed

●This test determines the exact site of any tubal blockage
●It also outlines the uterine shape to show any congenital abnormality or any distortion by fibromyomata
●Free spill of the dye, loculation around the distal end or frank occlusion of the tube often with club-shaped ending may be observed
●Minor peritubal adhesions may escape detection by hysterosalpingography

Question 21

What is a cervical compatibility test

Answer 21

●Cervical ovulatory mucus: copious, clear and shows spinnbarkheit
●After establishment of the corpus luteum and rise in blood progestrone it becomes scanty, viscid and cellular as it was in the early part of the cycle
●Sperm penetration of cervical mucus occurs more readily at the time of ovulation but can be hindered by sperm antibodies

Question 22

What is a post-coital test

Answer 22

This test is carried out at the time of ovulation ( day 14 of a 28-day cycle)
●6-12 h after intercourse, the cervix is exposed with a bivalve speculum and a sample of cervical mucus is withdrawn with a wire loop or pipette and placed on a warm slide and covered with a coverslip
●The number of progressively motile sperm in a number of high power fields is examined Normally a large number of active sperm will be seen
●When the test is negative it should be repeated in two further cycles at the time of ovulation as determined by the rise in basal body temperature

If all three tests are negative, a sample of the partner’s semen is obtained and a drop of it is placed alongside a drop of the woman’s ovulatory cervical mucus (Kurzrok-Miller test)

Question 23

What is the mucus invasion test

Answer 23

●If all three tests are negative, a sample of the partner’s semen is obtained and a drop of it is placed alongside a drop of the woman’s ovulatory cervical mucus (Kurzrok-Miller test)
●Invasion of the mucus by sperm is observed over the next 15 minutes
●Normal spermatozoa will immediately start to penetrate normal cervical mucus and will continue to be active in it
●A negative post-coital and mucus invasion test may be due to poor quality cervical mucus indicating a relative deficiency of oestrogen

●Presence of sperm auto-antibodies (♂) in seminal plasma causes clumping of sperm before ejaculation
●Sperm antibodies (♀) in cervical mucus cause agglutination and immobilization of the invading sperm.
●The serum of both partners should then be examined for sperm agglutinating and immobilizing antibodies

Question 24

What are some pathological causes of amenorrhea

Answer 24

Uterine lesions
•Ovarian lesions
•Pituitary disorders
•Disorders of other endocrine glands
•Psychiatric illness and emotional stress
•Severe general illness
•Drugs causing amenorrhoea
•Surgical operations or radiotherapy

Question 25

What uterine and ovarian lesions could cause amenorrhea

Answer 25

Uterine lesions:
●Rudimentary uterus, 1º
●Advanced pelvic tuberculosis 2º
Ovarian lesions:
●Ovarian dysgenesis 1º
●Stein-Leventhal syndrome (polycystic ovaries, failure of enzyme systems:  androstenedione) 2º

Question 26

What are some pituitary disorders that cause amenorrhea

Answer 26

●Pituitary infantilism (Levi-Lorain syndrome) 1º
●Ischaemic necrosis of anterior pituitary (Simmonds, Sheehan’s syndrome) All trophic hormones deficient 2º
●Acidophil tumours  acromegaly + later, amenorrhoea 2º
●Adenomata (prolactinomata) Prolactin  amenorrhoea 2º
●Stress Prolactin  amenorrhoea 2º

Question 27

How physical illness, emotional stress and drugs cause hormone fluctuations

Answer 27

Higher brain centres affect the function of the hypothalamus which in turn controls the output of gonadotrophins from anterior pituitary 2º
●Menstrual function may be suppressed temporarily during or after severe general illness or chronic illness (e.g. chronic renal failure) 2º
●Amenorrhoea may occur sometimes after stopping oral contraception with a spontaneous return of menstruation within 6 months or induction of ovulation with clomiphene 2º

Question 28

What are the two major sex hormones

Answer 28

●The 2 major sex steroid hormones are- Testosterone and Oestradiol
●Testosterone is the principal androgen synthesized by the testes in the male
●Oestradiol is the principal oestrogen secreted by the ovaries and concentration varies widely throughout the female menstrual cycle
●Progesterone is also produced by the ovaries and is secreted when the corpus luteum is formed after ovulation
●Testosterone and Oestradiol circulate in the plasma bound to SHBG

Question 29

What are ovarian hormones

Answer 29

Androgens are C-19 steroids synthesized by theca cells in the ovaries
●Androgens are converted by granulosa cells into oestrogens which are C-18 steroids. This involves aromatization of the A ring and loss of the C-19 methyl group
●The most important ovarian oestrogen is oestradiol
●The liver and subcutaneous fat convert adrenal and ovarian androgens to oestrone

Oestradiol and oestrone are both metabolized to the relatively inactive oestriol
●Development of female secondary sex characterstics and normal menstruation depend on oestrogens
●The main androgen secreted by the ovaries is androstenedione
●Androstenedione is converted to oestrone and to the more active testosterone in extra-ovarian tissues
●The ovaries secrete directly a small amount of testosterone
●Plasma concentrations of testosterone in women is about one tenth of that in men

Progesterone is secreted by the corpus luteum during the luteal phase of the menstrual cycle and by the placenta
●It prepares the endometrium of the uterus to receive a fertilized ovum
●It is necessary for the maintenance of early pregnancy
●It is pyrogenic and increases the basal body temperature

Question 30

What are testicular hormones

Answer 30

Testosterone is secreted by the Leydig cells, which are in the interstitial tissue of the testes between seminiferous tubules
●Production of tetosterone is stimulated by LH
●LH secretion is inhibited by testosterone by negative feedback
Inhibin is produced by the Sertoli cells which form part of the basement membrane of seminiferous tubules
●Inhibin controls FSH secretion by negative feedback
●Testosterone is involved in sexual differentiation, the development of secondary sexual characteristics, spermatogenesis and anabolism
In the male, the effects of testosterone depend on intracellular conversion to the more potent dihydrotestosterone (DHT) by the enzyme 5--reductase in target cells
●LH stimulates testosterone production from the Leydig cells
●Sertoli cells are involved in germ cell differentiation and spermatogenesis which are stimulated by FSH and depend on testosterone

Question 31

What is hyperprolactinaemia

Answer 31

Normal in pregnancy and lactation
●Samples for prolactin measurement should be taken at least 2-3 h after waking because levels are elevated during sleep
●The stress of venepuncture may also cause secretion of prolactin
●Macroprolactinaemia is caused by complex formation with immunoglobulins, and can be eliminated by precipitation of the complex with polyethylene glycol in the plasma sample
●It is an important cause of amenorrhoea, sexual dysfunction, and infertility
●It inhibits the normal pulsatile release of GnRH and gonadal steroid synthesis directly
●Plasma GnRH and oestrogens are low
●One third of patients have galactorrhoea