RAYMUNDO III D.

DOCE
NMD 3
DAVAO MEDICAL SCHOOL FOUNDATION
DEPARTMENT OF OBSTETRICS AND GYNECOLOGY

APRIL 24, 2020

TOPIC: 25 year-old with AMENORRHEA
(Student’s Copy)

CASE:

A 25-year-old G1 P0 (0-0-1-0) consulted because she had no menses for 8

months. In her first pregnancy, she underwent curettage due to a
miscarriage.
On PE, significant findings : BMI of 35 and presence of facial acne and
hirsutism.
Pelvic exam was normal.
Guide Questions:

1. What are the salient features of the case? (5 points)

o 25 year old
o G1P0 (0010)
o Amenorrhea for 8 months
o First pregnancy ended up to miscarriage
o Previously managed with curettage
o BMI of 35- falls under Obese II based on UP-PGH Family Medicine
Research Classification of Obesity
o Signs of hyperandrogenism: Facial acne and hirsutism
o Unremarkable pelvic exam

2. What additional information, if any, would you like to ask from the patient to obtain a
good impression? (10 points)

 Menstrual history such as:

 age of menarche
 cycle length and regularity
 days of flow
 number of pads changed per day
 passage of clots
 last menstrual period
 associated symptoms with menstruation
 Rule out pregnancy
 I will ask for any reliable pregnancy tests that the patient had
(although as a physician it is our duty to conduct confirmatory
tests and not just rely on outside laboratories)
 Other symptoms that would further suggest hyperandrogenism such as:
 Voice deepening
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 Hair loss in the scalp
 Seborrhea
 Acanthosis nigricans
 Eating habits, dietary lifestyle, exercise levels , and for presence of any
recent stressful events or illness
 Other comorbidities such as hypertension, diabetes mellitus, hyperthyroidism,
etc.
 Contraceptive history (any recent intake or discontinuation of oral
contraceptive pills or depot medroxyprogesterone acetate (DMPA)
 Associated signs of hypothalamic-pituitary disease such as:
 Headache
 Vertigo
 Visual disturbances
 Fatigue
 Polyuria
 Polydipsia
 Medication history of the patient, since some drugs can cause menstrual
irregularity or even amenorrhea such as:
 Danazol (or any androgenic drugs)
 High dose progestins
 Metoclopramide
 Phenothiazines
 Some cytotoxic agents
 History of obstetrical emergency like severe bleeding (since this can lead to
Sheehan’s syndrome) which can deprive the pituitary gland of enough
oxygen and can lead to amenorrhea
 Thoroughly investigate her history of endometrial curettage variable scarring
inside the uterine cavity, where in many cases the front and back walls of the
uterus stick to one another, a condition known as Asherman’s Syndrome
 Ask for history of tuberculosis as this can also potentially involve the genital
tract
 Past medical and surgical history
 Physical examination for any signs of genital ambiguities
 Family history of sexual abnormalities

3. Describe the Pubertal Rating according to Tanner stage. (10 POINTS)

The gold standard in pubertal development rating is the Tanner scale. This
method classifies puberty into five progressive stages considering changes that
occur independently in: a) size and shape of the breasts in girls and genitals in boys,
which reflect mainly activation of the hypothalamic-pituitary-gonadal axis; and b) the
distribution and characteristics of pubic hair in both sexes, which reflect increased
output of steroids due to the expansion of the adrenal zona reticularis.

Note: Photos shown below were taken from the internet.

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Female Breast Development
Thelarche is the term that describes the onset of breast development in
females.

STAGE DESCRIPTION PHOTO APPEARANCE

this is the prepubertal stage; the breast

Stage 1 has flat appearance with only papilla
(nipple) raised

the breast bud is present so that the

Stage 2 areola protrudes and areola begins to
widen

breast tissue extends past the areola

causing the elevation of the breast along
Stage 3
with the areola; the contour of the areola is
the same as the rest of the breast
areola forms a separate contour from the
rest of the breast creating what is referred
Stage 4
to as the "mound on the mound"
appearance

adult; areola flattens down assuming the

Stage 5
contour of the rest of the breast

Male Testis and Scrotum Development

Staging of male genital development is based primarily on changes in the
appearance of the penis and scrotum and not on testicular size, because testicular
size varies widely between individuals.

STAGE DESCRIPTION PHOTO APPEARANCE

prepubertal appearance; testes are less

Stage 1
than or equal to 1.5 cc in volume

Stage 2 scrotum becomes pendulous with the skin

becoming thinner; testicular volume is from
1.6 to 6 cc
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scrotum coarsens and the testes are 6 to

Stage 3
12 cc; penis lengthens

penis grows in length and circumference

Stage 4
and the testes are from 12-20 cc

adult appearance of penis, with testes that

Stage 5 are usually greater than or equal to 20 cc
in volume

Male and Female Pubic Hair Development

Pubarche refers to the onset of pubic hair growth. The term adrenarche is
broader, indicating the increased production of androgens by the adrenal glands.
Signs of adrenarche include pubic hair growth as well as other secondary sexual
hair (e.g., axillary and facial) and acne. Pubic hair rating is similar for both males
and females.

STAGE DESCRIPTION PHOTO APPEARANCE

prepubertal, lanugo may be present in

Stage 1
genital area but it is fine and downy
sparse growth of pubic hair in the midline,
Stage 2 mainly at the base of the penis or along the
labia majora
more hair grows so that it is visible from
Stage 3 several feet, along with coarsening and
increased pigmentation in some people

Stage 4 hair now makes a triangle over the pubis

adult; hair is outside of triangle, extending

Stage 5
up the abdomen and down the thighs

4. Differentiate Primary amenorrhea from secondary amenorrhea. (5 points)

Amenorrhea or absence of menstruation is has 2 classifications: Primary and

Secondary. Primary amenorrhea means that there is an absence of menses at the
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age of 14 without the development of secondary sexual characteristics or when
there is also an absence of menses at the age of 16 years with normal development
of secondary sexual characteristics. On the other hand, Secondary amenorrhea is
diagnosed when there is cessation of menses for at least 6 months or for at least 3
of the previous 3 cycle intervals in a woman who was previously menstruating.

5. What are the differential diagnoses? (15 POINTS)

CONGENITAL ADRENAL HYPERPLASIA

Rule in Rule out
 Signs of excessive amounts of
androgens May need to undergo test for 17-OH-
progesterone, and DHEAS. Elevated
 Facial acne
levels of 17-hydroxyprogesterone are
 Hirsutism
diagnostic of adult-onset congenital
 Amenorrhea and/or irregular menses adrenal hyperplasia.
 Normal internal reproductive organs

ASHERMAN’S SYNDROME
Rule in Rule out
 Patient does not experience severe
cramping abdominal pain
 History of curettage (secondary to  Normal pelvic exam as stated on the
miscarriage) case (no presence of hematometra
stated)
 Surgical trauma to the uterus
 Amenorrhea
Hysterosalpingography, hysteroscopy,
or sonohysterography can help confirm
or rule out the diagnosis.

CUSHING’S SYNDROME
Rule in Rule out
 Signs of excessive amounts of
androgens
 Facial acne Cannot be fully ruled out. Patient may
 Hirsutism be submitted to a 24 hour urine free
 Amenorrhea and/or irregular menses cortisol and Dexamethasone
 Normal internal reproductive organs suppression test as confirmatory.
 Obesity/weight gain

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HYPERPROLACTINEMIA
Rule in Rule out
 Patient does not manifest galactorrhea
 Amenorrhea and/or irregular menses which is a clinical feature of this
disease
 Facial acne
 This disease causes infertility, but is not
 Hirsutism
featured by the index patient
 25 years old (hyperprolactinemia is
common in reproductive age) Patient may need to undergo prolactin
serial sampling as a confirmatory test.

POLYCYSTIC OVARIAN SYNDROM (PCOS)

Rule in Rule out
 Signs of excessive amounts of
androgens
 Facial acne Cannot be fully ruled out. Patient may
 Hirsutism need to undergo ultrasound to look for
 Amenorrhea for 8 months the presence of 12 or more follicles in
 Normal internal reproductive organs each ovary or increased ovarian volume
 Obesity/weight gain >10 ml.
 25 years old (reproductive age)

6. What is the most likely impression? (5 POINTS)

Impression:
G1 P0 (0-0-1-0), Secondary amenorrhea probably secondary to ovarian dysfunction,
to consider Polycystic Ovarian Syndrome (PCOS).

Justification: The patient is a 25 year old G1P0 with a classic presentation of PCOS.
The patient meets the diagnostic criteria that requires two out of three following
signs and symptoms: oligomenorrhea/amenorrhea, hyperandrogenism (not
otherwise explained), or evidence of small multiple ovarian cysts on transvaginal
ultrasound. PCOS is a condition of unexplained hyperandrogenic chronic
anovulation associated with excessive estrogen.

7. What diagnostic examinations will be requested? Explain the rationale for requesting
the diagnostic examination. (5 POINTS)

DIANOSTIC EXAMINATION RATIONALE

This is done to verify and confirm for the
ULTRASOUND presence of any cystic formation in the
ovary.
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PREGNANCY TEST This is done to rule out pregnancy.
This is to rule out any other comorbidities
CBC, SERUM CHEMISTIRES,
and other systemic diseases.
URINALYSIS
This is to rule out hyperprolactinemia.
SERUM PROLACTIN LEVELS
Women with low FSH levels have a CNS
lesion or hypothalamic- pituitary failure,
SERUM FSH
elevated levels (>30mIU/mL have
Premature ovarian insufficiency
This is done to assess for the presence of
SERUM E2 excessive levels of estrogen which is
diagnostic for PCOS.
This is done to test for the presence of
INSULIN TOLERANCE TEST
hyperinsulinism which is a feature of PCOS.
to rule out lesion of hypothalamic- pituitary
CT/MRI region

ANTI-THYROID AND to check for possibility of autoimmune

ANTINUCLEAR ANTIBODY causes especially in younger women
LEVELS
to rule out mosaicism or a dysgenetic
KARYOTYPE
gonad, including possibility of Y cell line

8. What is Polycystic Ovarian Syndrome? Its Pathophysiology? Signs and Symptoms?

Its consequences? (20 POINTS)

Multiple causal factors have emerged in the pathophysiology of PCOS. It is

unclear which of these abnormalities triggers the vicious cycle of anovulation,
androgen excess, and hyperinsulinemia seen in PCOS. One of the primary
neuroendocrine defects described is alterations in gonadotropin secretion. There is
an underlying insensitivity of the hypothalamic gonadotropin-releasing hormone
(GnRH) secretion to ovarian steroids leading to increased luteinizing hormone (LH)
pulse amplitude and frequency.20 Low progesterone levels have also been
postulated to enhance the pulsatility of GnRH, leading to increased LH/follicle-
stimulating hormone (FSH) ratio. The relative increase in LH stimulates the ovarian
theca cells to secrete more androgenic precursors and androgens. The FSH
regulates the aromatase activity of the ovarian granulosa cells. Impaired FSH
synthesis and secretion leads to inadequate follicle development and reduced
aromatase levels. Hence there is a relative inability to aromatize androgenic
precursors to estrogen, which in turn results in preferential increase of ovarian
androgens

Women with PCOS have intrinsic abnormalities in ovarian theca cell

steroidogenesis resulting in hyperandrogenemia. In the ovarian theca cells,
androgen biosynthesis is mediated by cytochrome P-450c17 enzymes to form
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androstenedione. Androstenedione is then converted to testosterone by 17b-
hydroxysteroid enzyme or aromatized to form estrone.

There is intrinsic abnormality in gonadotrophin-releasing hormone (GnRH) pulse

generator leading to increased luteinizing hormone (LH) pulse amplitude and frequency
with relative impairment in follicle-stimulating hormone (FSH) secretion. Augmented LH
activity amplified by increased insulin drives the increased androgen production in the
ovarian theca cells with reduced aromatase levels. Hyperinsulinemia further inhibits the
production of sex hormone–binding protein (SHBG) in the liver, thereby increasing the
proportion of free testosterone compared with total testosterone.
The symptoms of PCOS includes irregular periods or no periods at all, difficulty
getting pregnant (because of irregular ovulation or failure to ovulate), excessive hair growth
(hirsutism) – usually on the face, chest, back or buttocks, weight gain, thinning hair and
hair loss from the head and oily skin or acne. The long term consequences of Polycystic
Ovarian Syndrome are weight gain/obesity and metabolic syndrome, type 2 diabetes, and
depression and mood swings. Women with PCOS have a high blood pressure and high
cholesterol – which can lead to heart disease and stroke. With increase in aging there are
risks of cancer, particularly endometrial and ovarian cancer. Endometrial cancer can begin
at a younger age due to long term anovulation and unopposed estrogen stimulation of the
endometrium.

9. What are the Criteria for the Diagnosis of Polycystic Ovarian Syndrome according to
National Institute of Health and Human Development (1990), ESHRE-ASRM 2003
and AEPCOS 2012? (10 POINTS)

National Institute of Child  Menstrual irregularity

Health and Human  Hyperandrogenism (clinical and biochemical)
Development (NICHD)
1990 This requires both criteria
European Society of  Oligoanovulation and/or anovulation
Human Reproduction and  Clinical and/or biochemical signs of
Embryology/American hyperandrogenism
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Society of Reproductive
 Polycystic ovarian morphology by ultrasonography
Medicine 2003
This requires 2 out of 3 criteria
Rotterdam Criteria
 Clinical and/or biochemical signs of
hyperandrogenism
 Ovarian dysfunction (oligoanovulation and/or
polycystic ovarian morphology)
 Exclusion of other causes of hyperandrogenism

These 3 diagnostic criteria identified different

Androgen Excess and phenotypes of women with PCOS. Although the NIH
PCOS Society (AEPCOS) criteria identified the hyperandrogenic women who
2006 are at higher metabolic risk, the Rotterdam criteria
also identified women with ovulatory dysfunction and
polycystic ovarian morphology. Most recently, in
December 2012, the NIH sponsored an expert panel
that endorsed the acceptance of the Rotterdam
criteria because they encompass a broad spectrum of
phenotypes representing PCOS.

 Excess androgen activity

 Oligoovulation/anovulation and/or PCOM
Androgen Excess and
PCOS Society (AEPCOS)  Exclusion of other entities that would cause
2014 excess androgen activity

This requires all criteria

 Endorsed the adoption of the Rotterdam criteria
National Institute of Health for convention and familiarity, acknowledged its
(NIH) 2012 limitations, and suggested a more appropriate
name for PCOS.

10. How will you manage this case? (15 POINTS)

Goals of treatment include minimizing hyperandrogenic symptoms, prevention of

endometrial hyperplasia, and addressing the underlying metabolic risk factors to
delay type 2 diabetes. Women desiring pregnancy may need assistance with
ovulation induction therapy.

Combined oral contraceptives (but should be monitored well since the

patient is obese and OCP might predispose her to additional morbidities such
as cardiovascular risks)

Action: In women who do not desire pregnancy, hormonal contraceptives

(estrogen/progestin combinations) remain the first line of treatment of
hirsutism and acne. The progestin component in oral contraceptives (OC)
inhibits LH secretion, thereby reducing the LH-dependent androgen
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production This treatment plays a major role in regulating dysfunctional
bleeding, limiting unopposed estrogen (thereby decreasing the risk of
endometrial cancer), increasing sex hormone-binding globulin (hence
decreasing free androgen levels), and suppressing ovarian androgen
production. The progestin component of OC pills bind with progesterone and
androgen receptors. The first-generation progestins, norethindrone and
norethindrone acetate, are possible options in women with PCOS for
hyperandrogenism

Weight loss through diet and exercise

Action: Weight loss from dietary interventions and exercise forms the first line
of management in obese women with PCOSA modest weight loss (even as
low as 5%) has been found to lower androgen levels, improve hirsutism,
normalize menses, and decrease insulin resistance. Although there is a
paucity of large randomized trials showing exercise benefits in PCOS
populations, there is overall evidence of the benefits of exercise in reducing
the risk of metabolic disease

Insulin-sensitizing agents (such as Metformin)

Action: This drug can potentially reduce insulin resistance and improve
ovulatory function. This treatment also limits the risk of developing
cardiovascular disease and diabetes mellitus.

Aromatase inhibitors such as letrozole

Action: Letrozole blocks the conversion of androgens to estrogen. Therefore,

there is less negative feedback on the hypothalamus leading to increased
levels of GnRH and thereby FSH. Letrozole is usually used in women
resistant to clomiphene citrate or who have side effects from clomiphene,
such as vasomotor symptoms, headaches, and thin endometrium. A recent
NIH-sponsored clinical trial showed a significant increase in live births with
letrozole compared with clomiphene in women with PCOS, adding letrozole in
the treatment armentarium.

Antiandrogens (such as Spironolactone and Cyprosterone acetate)

Action: Spironolactone, an aldosterone antagonist, inhibits androgen receptor

and 5a-reductase activity. It is usually started at 50 mg once daily and
increased to 100 mg twice daily. It rarely results in hyperkalemia, although
menstrual irregularities are seen at higher doses, and it is usually used in
combination with the OC pill. Potassium levels are usually measured 4 to 6
weeks after initiating therapy and after dose escalation. Spironolactone is
teratogenic and causes feminization of male fetal genitalia. Therefore, it
should be used with adequate contraceptive coverage in women of
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childbearing age. Cyproterone acetate (CPA) has antiandrogen activity at the
level of androgen receptor and suppresses serum gonadotropins and
androgen levels. It is administered for the first 10 days of the menstrual cycle
at a dose of 50 to 100 mg/dl.

Eflornithine

Action: Eflornithine is an irreversible inhibitor of ornithine decarboxylase, an

enzyme involved in hair follicle formation. Topical therapy with eflornithine
hydrochloride cream helps to reduce the rate of hair growth. Patients need to
be advised that the hair growth returns on discontinuing the treatment.

Thank you!

-END OF CASE STUDY-