Session 3: Puberty and Abnormalities of Menstruation

Question 1

When does puberty normally occur?

Answer 1

• Primary sexual characteristics are established before birth. Whilst hormonal changes occur in the male in the first few months of life, the male and female reproductive systems remain inactive until puberty (remain inactive for at least 9-10 years, often more)
• The timing of puberty varies between the sexes and between individuals, but in each sex there is a fixed sequence of events. So the sequence of events is age variable but order consistent, allowing us to judge how far through the process someone is – able to determine whether puberty is progressing normally.
• On average, girls reach puberty before boys (8-13 years for girls, 9-14 years for boys).
• Obvious signs of puberty are preceded by a series of events that depend upon sex steroids secreted from the gonads and adrenal glands

Question 2

Describe the Growth Spurt

Answer 2

The Growth Spurt: marked acceleration of growth in both boys and girls

[*] Starts later in boys (earlier and faster initially in girls)

[*] Velocity about 9cm/year in girls and 10cm/year in boys

[*] Adult males end up larger because boys grow more before the growth spurt and slightly more during it – their growth spurt is longer and slightly faster; girls begin and end puberty before boys.

[*] The growth spurt is terminated by epiphyseal fusion, at which point adult height is virtually set. If puberty is precocious, epiphyseal fusion occurs much earlier – adult statue is shorter than expected

Question 3

Describe the development of Secondary Sexual Characteristics

Answer 3

The secondary sexual characteristics such as breasts, genitalia and pubic hair also develop under the influence of sex steroids.

[*] Female: gonadal oestrogens influence breast development and female genital development, whereas pubic hair and axillary development is controlled by androgens from the adrenals.

[*] Male: testicular androgens control development of genitalia and body hair and deepening of the voice.

Question 4

What is the defining event of puberty for girls? And its equivalent in boys?

Answer 4

• A defining event in puberty for girls is the first menstrual bleed – menarche.
• The equivalent event in boys, which is much less easy to monitor, is occurrence of nocturnal erection and the first ejaculation.
• Neither event indicates the onset of full fertility

Question 5

Describe the sequence of events in girls

Answer 5

[*] Breast bud (thelarche) (8-11 years) (first sign puberty has begun)

[*] Pubic hair growth begins (adrenarche) (11-12 years)

[*] Growth spurt (9cm/year)

[*] Onset of menstrual cycles (menarche)

[*] Pubic hair adult

[*] Breasts adult

Question 6

Describe the sequence of events in boys

Answer 6

Puberty – boys (9-14 years)

[*] Genital development begins

[*] Pubic hair growth (adrenarche)

[*] Spermatogenesis begins

[*] Growth spurt (10cm/year)

[*] Genitalia adult

[*] Pubic hair adult

Question 7

Describe hormonal changes underlying puberty

Answer 7

Hormonal changes: onset of puberty is associated with steady rise in FSH and LH secretion

[*] In girls, plasma levels of FSH and LH rise gradually from about 7 years of age to reach adult levels at or soon after menarche. Plasma oestrogen levels rise steadily, until at the beginning of menstrual cycles regular cyclical rises and falls are associated with the ovarian cycle.

[*] In boys, FSH and LH levels rise later, to reach adult levels around 16 years of age, associated with steady rises in testosterone levels.

[*] In both males and females, weak androgens are secreted from the adrenal cortex.

Question 8

Describe the initiation of puberty

Answer 8

[*] The anterior pituitary gonadal axis is capable of responding to stimulation by GnRH long before puberty normally occurs but GnRH secretion is low.

[*] Most parts of the reproductive system can work before normal age of puberty (precocious puberty) but don’t because hormone levels are low (due to low GnRH secretion)

[*] Puberty occurs when the brain initiates pulsatile GnRH secretion so the brain controls the timing of puberty. This does not seem to depend on any signal from the gonads.

• It was once thought that the pre-pubertal hypothalamus was very sensitive to negative feedback by gonadal steroids, so very low circulating levels inhibited completely the secretion of GnRH. Puberty would then arise from gradually decreasing hypothalamic sensitivity to feedback. (Reduction in sensitivity to negative feedback by steroids)
• An alternative and now thought more likely, explanation is that the hypothalamic mechanisms ‘mature’ and steadily secrete more GnRH under other influences. (Maturation of central mechanisms).
• Either way various factors influence the timing of puberty. First, puberty has become steadily earlier in western societies over the past 150 years. In 1830 girls in Norway reached menarche at 17 years of age, now it occurs at an average, age 13.

Question 9

What is the main factor in influencing puberty? What other factors are there?

Answer 9

[*] The main determining factor influencing puberty is body weight.

• The body weight at menarche is about 47kg in girls and that at the beginning of the growth spurt is 30kg. If body weight falls significantly below this, reproductive cycles cease (may be signalled to the brain by leptins)
• In boys, the critical weight is about 55kg.
• The plasma concentration of a fat-derived hormone – leptin – may indicate to the hypothalamus the attainment of the initial body weight.

[*] In many species where breeding is seasonal, GnRH secretion is switched on and off by changes in daylight, influencing the pineal gland and reflected in changes in the secretion of melatonin => new ‘puberty’ each year

[*] Precocious and delayed puberty in humans can be associated with various CNS disorders such as meningitis and tumours. Pineal tumours can influence puberty in humans

Question 10

What does pubic hair and breast development depend on?

Answer 10

Pubic and Axillary hair

[*] Depends on androgens in both sexes (from the adrenals in girls)

Breast development:

[*] Depends on oestrogens

[*] Each mammary gland comprises lobulated masses of glandular tissue. Glandular tissues are embedded in adipose tissue and separated by fibrous connective tissues. Each of the lobes contains lobules of alveoli, blood vessels and lactiferous ducts. Ovarian oestrogens, at the onset of pregnancy, induce growth of the lactiferous duct system. The ducts branch as they grow and their ends form into small, solid, spheroidal cell masses will form the lobular alveoli. The breast and alveoli enlarge.

[*] With menarche, cyclic oestrogen and progesterone secretion begin and an extra phase of ductal and rudimentary lobular growth will occur. Adrenal corticosteroids further enhance duct development. The breasts continue to increase in size for some time after menarche due to deposition of fat and additional connective tissue. Final breast differentiation and growth will not occur until pregnancy.

Question 11

What does the growth spurt depend on? What does genital development in boys depend on?

Answer 11

Growth Spurt:

[*] Depends on growth hormone and steroids in both sexes

[*] Oestrogen closes epiphyses earlier in girls (so growth spurt is earlier and shorter). Oestrogen is needed to initiate the growth spurt, but once levels reach a certain point it causes the epiphyses to fuse.

**Genital development in boys depends on testosterone **

Question 12

What is Precocious Puuberty?

Answer 12

[*] Signs of puberty before age of 8 :

• Menstruation before age 10 years
• Secondary sexual characteristics before age 8 years (girls)
• Secondary sexual characteristics before 9 years (boys)

Question 13

What causes Precocious Puberty?

Answer 13

[*] The cause of the majority of precocious puberties is unknown but can be due to

• Neurological: early stimulation of central maturation which could be caused by pineal tumours (pineal gland secrets melatonin) or meningitis => early, inappropriate GnRH secretion
• Uncontrolled gonadotrophin or steroid secretion which could be caused by hormone-secreting tumours

Question 14

What is the normal length of the menstrual cycle?

Answer 14

21-35 days

Question 15

Describe pre-menopause including hormonal and menstrual cycle changes

Answer 15

[*] Typically from age around 40 years

[*] Changes in menstrual cycle

• Follicular phase shortens – ovulation early or absent
• Less oestrogen secreted
• LH and FSH levels rise due to less negative feedback – FSH more due to reduced Inhibin feedback
• Reduced fertility (although still possible to get pregnant)

Question 16

What happens during menopause?

Answer 16

Female reproductive life ends with the menopause. This occurs around 49-50/51/52years of age but variable, and is associated with the depletion of follicles in the ovaries. Lasts 2-8 years.

[*] Cessation of menstrual cycles is not controlled by the brain like puberty, but is associated with the ovaries running out of follicles. No more follicles develop.

[*] Oestrogen levels fall dramatically.

[*] Less negative feedback so LH and FSH levels rise.

[*] FSH rises dramatically due to loss of Inhibin too. Before the menopause, LH levels are higher than FSH but after the menopause, FSH levels are higher

Gonadotrophins are no longer able to stimulate follicular development, so the interaction between the hypothalamus, pituitary and gonads that maintains reproductive cycles is broken.

No more follicles develop.
Oestrogen and progesterone levels fall dramatically producing a wide variety of physiological effects including vaso-motor changes (‘hot flushes’), mood changes and others.

Question 17

What are the effects of the menopause?

Answer 17

[*] Vascular changes – ‘hot flushes’

• Affect around 80% to some degree
• Transient rises in skin temperature and flushing
• Relieved by oestrogen treatment (so must be due to decrease in oestrogen)

[*] On oestrogen sensitive tissues (reproductive apparatus shrinks)

• Uterus: regression of endometrium, shrinkage of myometrium. The uterus shrinks away into a very small organ.
• Thinning of the cervix
• Vaginal rugae lost – becomes thinner, less distensible
• Involution of some breast tissue
• Changes in skin
• Changes in bladder – reduction in bladder tone

Lower oestrogen levels may also be associated with the development of osteoporosis

[*] Bone mass reduces by 2.5% per year for several years – get thinner progressively

[*] Increased reabsorption relative to production

[*] Osteoporosis – much greater in some than others and is a major reason for fractures in later life but can be limited by oestrogen therapy.

Question 18

Is there a male menopause?

Answer 18

Whether there is a ‘male menopause’ or ‘andropause’ is debatable.

[*] No obvious event

[*] Spermatogenesis continuous throughout life (new fathers in 60s and 70s not uncommon) but incidence of loss of libido, impotence and inability to reach orgasm increase with age.

[*] Testosterone levels may decrease but without rise in LH (or FSH) suggesting a change in the feedback control mechanism.

Question 19

List the advantages and disadvantages of hormone replacement therapy in the post-menopausal woman

Answer 19

• Relieves symptoms of the menopause
• Can improve well-being
• Oestrogen given orally or topically by patch or gel
• Can limit osteoporosis
• Current advice no longer recommended for first line protection (bisphosphonates now recommended)
• Not advised for cardioprotection

Question 20

What is the average blood loss during a period? What does Dysmenorrhoea andd Oligomenorrhoea mean?

Answer 20

• There is no such thing as an average blood loss during a period as it varies for all women – but generally average is 30-45ml
• Dysmenorrhoea: painful periods
• Oligomenorrhoea: uterine bleeding (infrequent periods) occurring at intervals between 35 days and 6 months

Question 21

Describe Premenstrual Syndrome

Answer 21

Pre menstrual syndrome: certain symptoms occur each month before a period.

[*] Psychological symptoms include tiredness, irritability, tension, feelings of aggression/anger, low mood, anxiety, loss of confidence, feeling emotional, changes in sleep pattern, appetite etc

[*] Physical symptoms include breast swelling and/or pain, abdominal bloating, swelling of the feet or hands, weight gain, an increase in headaches etc

Question 22

Define DUB, Ovulatory and Anovulatory Cyles & Cryptomenorrhoea

Answer 22

• Dysfunctional Uterine Bleeding (DUB): abnormal bleeding, no obvious organic cause, usually anovulatory
• Ovulatory vs Anovulatory cycles:

[*] Anovulatory: no ovulation/luteal phase, oligo or amenorrhoea +/- menorrhagia (heavy bleeding)

[*] Ovulatory: regular menstrual cycles (plus premenstrual symptoms such as dysmenorrhoea and mastalgia (breast pain/sore breasts))

• Cryptomenorrhoea: periods occur but not visible due to obstruction in outflow tract.

Question 23

Discriminate between primary and secondary amenorrhoea

Answer 23

• Amenorrhoea – absence of periods for at least 6 months
• Primary Amenorrhoea: absence of menses (never had a period) by age 14 with absence of secondary sexual characteristics (SSC) e.g. breast development, or absence by age 16 with normal SSC
• Secondary Amenorrhoea: where an established menstruation has ceased – for three months in a woman with a history of regular cyclic bleeding or nine months in a woman with a history of irregular periods. This usually happens to women aged 40-55 years.

Question 24

Describe hypothalmic/pituitary origins/causes of Amenorrhoea

Answer 24

• Pituitary and hypothalamic / central regulatory disorders
• Generally, inadequate levels of FSH lead to inadequately stimulated ovaries which then fail to produce enough oestrogen to stimulate the endometrium (uterine lining), hence amenorrhoea. In general, women with hypogonadotrophic amenorrhoea are potentially fertile.
• Both hypothalamic and pituitary disorders are linked to low FSH levels leading to hypogonadotrophic amenorrhoea.

Question 25

Give primary and secondary hypothalmic and pituitary disorders leading to Amenorrhoea including Kallmann Syndrome and Sheehan Syndrome

Answer 25

* *Primary Hypothalamic disorders: Kallmann syndrome** – developmental abnormality of the CNS in which those neurosecretory cells destined to become the GnRH pulse generator **fail to migrate from their origins in the olfactory placode to the hypothalamus** =\> inability to produce GnRH (and FSH subsequently) * *Secondary Hypothalamic disorders:** * Exercise amenorrhoea, related to physical exercise (exercise alters the HPA axis) * Stress amenorrhoea * Eating disorders and weight loss (obesity, anorexia nervosa or bulimia). Fall below critical weight (\<47kg) menses will cease **Secondary Pituitary Disorders** * Large pituitary tumours can compress the optic chiasm (the crossing point of the optic nerves), leading to vision loss and can also compress the normal anterior pituitary gland, leading to pituitary failure/dysfunction * **Sheehan syndrome (hypopituitarism caused by ischaemic necrosis of the anterior pituitary due to blood loss and hypovolaemic shock during and after childbirth)** * Hyperprolactinaemia * Haemochromatosis – ‘Iron overload’ Other secondary central regulatory disorders: hypo or hyperthyroidism

Question 26

Give Gonadal/End Organ origins of Amenorrhoea

Answer 26

[\*] Ovarian: Gonadal/End Organ Amenorrhoea. The ovary does not respond to pituitary stimulating, giving low oestrogen levels. The lack of negative feedback from oestrogen levels leads to elevated FSH levels in the menopausal range (hypergonadaotrophic amenorrhoea) Chromosome testing is usually indicated in younger individuals with hypergonadotrophic amenorrhoea. Low oestrogen levels are seen in these patients and the hypo-oestrogenism may require treatment

Question 27

Give Primary Gonadal/End-Organ Disorders

Answer 27

* Gonadal dysgenesis including Turner syndrome. Most common cause. Girls with Turner syndrome (45, X) typically have dysfunctional ovaries. * Androgen insensitivity syndrome (Testicular feminization syndrome) – Individuals are phenotypically girls and will develop breasts because the androgens secreted by their overstimulated testes can be converted peripherally to oestrogens. However they do not have a uterus and therefore cannot menstruate. * Receptor abnormalities for hormones FSH and LH * Specific forms of congenital adrenal hyperplasia

Question 28

Give Secondary Gonadal/End-Organ Disorders including PCOS

Answer 28

* **Pregnancy (most common cause)** * Anovulation (no ovulation occurs) * Menopause * Premature menopause * Polycystic ovarian syndrome (PCOS) – most common cause of **chronic anovulatory amenorrhoea**. PCOS pathophysiology can be linked to the combination of exaggerated pulsatile GnRH secretion, causing elevated circulating luteinizing hormone (LH) and increased LH/FSH ratio, and defects in insulin signalling for glucose transport and lipolysis causing insulin resistance. Ovarian theca cells respond to LH by increasing cholesterol conversion to androgens. PCOS is characterised by amenorrhoea or oligomenorrhoea, physical signs of hyperandrogenism (hirsuitism, acne) and the presence of enlarged polycystic ovaries. * Drug-induced

Question 29

Give Outflow Tract origins and causes of Amenorrhoea

Answer 29

**[\*] Outflow tract i.e. uterus, vagina, cervix** * The hypothalamic-pituitary-ovarian axis is functional therefore FSH level is normal. **Primary Causes:** * Uterine: Mullerian agenesis (second most common cause, 15% of primary amenorroea) – complete absence of the female internal genitalia including the vagina, uterus and fallopian tubes in a chromosomally normal female. * Vaginal: vaginal atresia, cryptomenorrhoea (condition when menustration occurs but is not visible due to an obstruction of the outflow tract), imperforate hymen **Secondary Causes:** * Intrauterine adhesions (scar tissue), which typically develop after uterine surgery (Asherman’s syndrome)

Question 30

Describe the aspects of taking a history in evaluating amenorrhoea

Answer 30

[\*] Menstrual history Ever had one before? What was your cycle like before? [\*] Contraception [\*] Pregnancy [\*] Surgery [\*] Medication [\*] Weight change [\*] Chronic diseases, stress, diet etc [\*] Family history: ask about siblings, parents, chronic conditions * Age at menopause * Thyroid dysfunction * Diabetes * Cancer

Question 31

Describe the physical examination for amenorrhoea

Answer 31

* BMI – weight change * Hair distribution – PCOS (=\> hirsuitism) * Thyroid * Visual fields / Breast-discharge (Hyperprolactinaemia) * Abdomen-masses? Tenderness?

Question 32

Describe the management of Amenorrhoea

Answer 32

[\*] History [\*] Remember to always rule out pregnancy [\*] History and examination suggests * Ovarian-axis problem: TSH, prolactin, FSH, LH * Hirsuitism (excessive hair growth) - Testosterone, Dehydroepiandrosterone (DHEAS), androstenedione and 17-OH progesterone * Chronic disease – ESR (erythrocyte sedimentation rate), LFT’s (liver function tests) * CNS – MRI (to look for pituitary adenoma) [\*] The management of amenorrhoea varies widely depending on the cause. If due to insufficiency in a hormone, the amenorrhoea may be treated with hormone replacement. If due to lifestyle (e.g. exercise, weight loss), can be treated by modifying these factors.

Question 33

What are common causes of menorrhagia

Answer 33

Menorrhagia: heavy periods - excessive (\>80ml) uterine bleeding, prolonged (\>7 days) regular [\*] Heavy vaginal bleeding that is not DUB [\*] Usually secondary to distortion of uterine cavity – heavy with or without prolongation (anatomical) * Uterus unable to contract down on open venous sinuses in the zona basalis [\*] Other causes organic, endocrinologic, haemostatic and iatrogenic [\*] **Fibroids** are benign smooth-muscle-cell-derived growths in the uterus vary in size. They are common and normally asymptomatic but can cause heavy or painful periods. Fibroids are sensitive to oestrogen and progesterone, and tend to swell when levels of these hormones are high and shrink when levels are low. They increase the surface area of the endometrium. [\*] Usually ovulatory

Question 34

Describe the management of menorrhagia

Answer 34

* History * Physical exam – anaemia, obesity, androgen excess e.g. hirsuitism, acne, ecchymosis/purpura, thyroid, galactorrhoea, liver/spleen, pelvic – uterine, cervical and adnexal [\*] NB: physical examination for anaemia is not particularly accurate – perhaps only 50% of the time **Management – usually with progesterone, focus on dealing with the symptoms** 1. Tranexamic acid (1g QDS) or NSAIDs (Mefanamic Acid 500mg TDS) or Combined oral contraceptive pill 2. Norethisterone (15mg) daily from days 5 to 26 of the menstrual cycle, or injected long-acting progestogens 3. Levonorgestrel-releasing IUS provided long-term (at least 12-months use is anticipated). (If hormonal treatments are not acceptable to the woman, than either tranexamic acid or NSAIDs can be used).

Question 35

What is DUB?

Answer 35

**Dysfunctional Uterine Bleeding (DUB): excessively heavy, prolonged or frequent bleeding of uterine origin that is not due to pregnancy, pelvic or systemic disease** [\*] Diagnosis of exclusion – other potential causes for the bleeding must be ruled out: * HCG, TSH – exclude pregnancy, thyroid * Coagulation workup * Smear if appropriate – exclude cancer * Sample endometrium [\*] Anovulatory – 90% of DUB occurs when ovulation is not occurring. The corpus luteum does not form to release progesterone. As a result oestrogen is produced continuously, causing overgrowth of uterine lining and subsequent bleeding. [\*] 10% of DUB occurs when ovulation is occurring, but progesterone secretion is prolonged because oestrogen levels are low. This causes irregular shedding of the uterine lining and erratic bleeding. [\*] Usually extremes of reproductive life and in patients with polycystic ovary syndrome (PCOS)

Question 36

Describe the pathophysiology and management of DUB

Answer 36

**[\*] DUB Pathophysiology:** * Disturbance in the HPO axis thus changes in length of menstrual cycle * No progesterone withdrawal from an oestrogen-primed endometrium * Endometrium builds up with erratic bleeding as it breaks down. **[\*] DUB Management** * HCG, TSG * ? Coagulation workup * Ensure smear if appropriate (think about haematological causes) * \>35 or Calcium risk factors, tamoxifen use – sample endometrium (consider malignancy) * I/V or I/M conjugated oestrogen therapy acute DUB * Usually followed by oral contraceptive pill (OCP) or progestogen (class of steroid hormones that bind and activate the progesterone receptor) * Cyclic progestogens for 10 to 12 days each cycle, consider mirena IUD (levonorgestrel-releasing intrauterine device 0 type of long-acting birth control) * OCP (oral contraceptive pill) * D and C – old school, no longer recommended