Case 6

Villegas, Jose Bernabe GYNECOLOGY Vinluan, Joseph David Q. Dr. Teresa Luna Wong, Deo Adiel 2007 Yague, Glenn 3rd Year-D4 Yang, Caprice

July 12,

CASE #6 23 year old single nulligravid, 4th year medical student consulted because of irregular menses since 16 years of age. LMP: July 5-8, 2007; PMP: 3 months ago and noted that her menses were heavier than usual. Family History: (+) DM – parents; PPE: Height – 5 feet, Weight – 150 lbs.; HEENT – bushy eyebrows, pink conjunctiva with coarse hair in the upper lip, no anterior neck mass; Breasts - well developed, symmetrical, coarse hair around the areolar area; Abdomen: hair along the linea nigra, flabby, soft, no masses and tenderness; External Genitalia: coarse pubic hair extending down to the perianal area and medial aspects of the thight; intact hymen; Rectal exam: cervix – firm, long, Uterus & adnexae – not well palpated due to thick abdominal wall; Extremities: increased hair distribution on both lower extremities. 1. What other data from the history should one ask for? History of Present Illness: a) Ask about any accounts of milky discharge – this might be helpful especially when considering hypothalamic causes of irregularities in menses. b) Sexual History – ask the patient if there had been any history of trauma that might be attributed to mechanical causes of bleeding. This can also be asked in the Past Medical History as part of possible hospitalizations because of any injuries. c) Current medications – Inquire about intake of exogenous steroids which may cause Cushing syndrome (acne, buffalo hump, moon facies, etc). Certain medications such as Busulfan, Chlorambucil, Cyclophosphamide, Phenothiazines, Oral contraceptives, Non-oral contraceptives such as Depo-Proveracan can cause irregularities in menses. Moreover, the patient is exemplifying a condition called hirsutism. There are also medications that could be attributed to the hairiness such as Minoxidil, Phenytoin, Cyclosporine, Diazoxide, Penicillamine, Heavy Metals, Acetazolamide etc.

d) Menstrual history – try to establish the magnitude of irregularity (say, the span between menses) in three to four accounts of menses. This may rule in/out imbalances in hormones, chronic anovulation or just purely genetic causes of the timing of menses. Afterwhich, ask the quantity of menses for every period. This might be particularly helpful in delineating disorders, especially endocrinologic disorders, with amenorrhea, oligomenorrhea and meno/metro/menometrorrhagia as presenting signs. Also, ask for constitutional symptoms accompanying menses like pain, headaches, etc. which may be helpful when you are considering possible concomitant illness/es that would cause the bleeding disorder. Past Medical History: a) Gynecologic history – review the woman's history of past gynecologic disorders if there had been any for possible complications that cause bleeding or hirsutism such as androgen-producing tumors. b) Surgery or procedures – The patient is nulligravid and 23 years old at that, at the back of our minds, we might want to consider if there had been any undocumented or undivulged pregnancy in which there had been any procedure done to terminate it. This "procedure" might adversely affect the female genital tract. Furthermore, uneducated personnel might have taken part and further complications might be of consequence contributing to the present scenario. •

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Personal History: Inquire about patient’s work load and personal activities. o Severe weight loss probably due to anorexia nervosa could lead to lack of normal hypothalamic stimulation. Typically, menses ceases when body weight falls to 85% of the ideal for age and height, the result of hypothalamic dysfunction related to the weight loss itself and exacerbated by excessive exercise and stress. Anxiety and emotional distress can also cause a missed period. – stress, diet, and increased exercise may decrease pulsatility of GnRH secretion. o Moreover, work-related stress may also be an important factor in irregularities in menses. The patient, a medical student, as it is, is under a lot of stress (readings, papers etc.) Family History: menopausal age of ascendants, familial diseases (e.g. PCOS, idiopathic hirsutism, CAH), endocrine abnormalities (e.g. DM, thyroid abnormalities, etc.), hirsutism, hypertrichosis. All of which might point to a genetic cause of irregular menses that deserves further consideration.

Review Of Systems: o Any serious headaches, visual changes or galactorrhea in association with amenorrhea may point to hypothalamic/ pituitary disorders. o Any history of polyphagia, polydipsia, polyuria because DM and obesity is closely associated with irregularities in the menstrual cycle. o Accompanying symptoms like hot flashes, breast atrophy, vaginal dryness & decreased libido may be present along with amenorrhea. If patient had experienced these symptoms, premature ovarian failure should be considered. o Thyroid enlargement, heat-cold intolerance or palpitations pointing to hyperthyroidism. In this condition, decreased levels of SBHG and increased free testosterone levels may result to hirsutism. Physical Examination: o Hirsutism: Patients may have excessive body hair in a male distribution pattern and acne. Some patients have virilizing signs, such as male-pattern balding or alopecia, increased muscle mass, deepening voice, or clitoromegaly; these findings should prompt a search for other causes of hyperandrogenism. o Obesity: Approximately 50% of women with PCOS have abdominal obesity characterized by a waist circumference of greater than 35 in. (> 88 cm). o Acanthosis nigricans: This is a diffuse, velvety thickening and hyperpigmentation of the skin. It may be present at the nape of the neck, axillae, area beneath the breasts, intertriginous areas, and exposed areas (eg, elbows, knuckles). In patients with PCOS, acanthosis nigricans is thought to be the result of insulin resistance. o Patients with signs and symptoms of metabolic syndrome may have elevated blood pressure with a systolic blood pressure of 130 mm Hg or higher and diastolic blood pressure of 85 mm of Hg or higher. Metabolic diseases may adversely affect timing of menses and numerous patients with PCOS have characteristics of metabolic syndrome. o In women, metabolic syndrome is characterized by abdominal obesity (waist circumference > 35 in.), dyslipidemia (triglyceride level >150 mg/dL, high-density lipoprotein cholesterol [HDL-C] level < 50 mg/dL), elevated blood pressure, a proinflammatory state characterized by an elevated C-reactive protein level, and a prothrombotic state characterized by elevated PAI-1 and fibrinogen levels 2. What diagnostic procedures should be requested?

Pregnancy test should be done to rule out possibility of pregnancy especially for women of childbearing age presenting with irregular menses or amenorrhea. However, our patient has an intact hymen based from the PE. To rule out causes of anovulation other than pregnancy, the following diagnostic procedures may be done if further inquiry is wanted. Otherwise, these are optional: o Free testosterone level is a sensitive indicator of androgen excess in PCOS. However, a level higher than 150 ng/dL may also indicate ovarian and adrenal tumors. o Sex hormone-binding globulin (SHBG) levels are usually low in patients with PCOS. Furthermore, lower levels of SHBG increase the availability of free testosterone which could lead to hirsutism. o Dehydroepiandrosterone-sulfate (DHEA-S) is a marker of adrenal androgen production and may be normal or slightly above the normal range in patients with PCOS. Levels greater than 800 mcg/dL may indicate ovarian and adrenal neoplasms. o Serum 17-hydroxyprogesterone levels after a cosyntropin stimulation test – To rule out late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. A 17hydroxyprogesterone level of less than 1000 ng/dL, as measured 60 minutes after cosyntropin stimulation, rules out late-onset congenital adrenal hyperplasia. o 24-hour urine sample for free cortisol and creatinine – to rule out Cushing’s syndrome. Levels of urinary free cortisol that are 4-fold the upper limit of normal are diagnostic for Cushing syndrome. o Free T3 and T4 – to rule out any thyroid abnormalities (ie. Hypothyroidism) o FSH level should be checked to rule out primary ovarian failure. o 75-g oral glucose-tolerance test (OGTT) - performed because of the high prevalence of impaired glucose tolerance and type 2 diabetes mellitus in women with PCOS. A 2-hour postload glucose value of less than 140 mg/dL indicates normal glucose tolerance, a value of 140-199 mg/dL indicates impaired glucose tolerance, and a value of 200 mg/dL or higher indicates diabetes mellitus. Radiologic evaluation: Ovarian ultrasonography, preferably accomplished by using a transvaginal approach, can be performed to assess ovarian morphology. Ultrasonographic evaluation may be a useful method for the early detection and subsequent follow-up of PCOS. Generally, ovarian size is increased. The most important ultrasonographic finding is bilaterally increased number of microcysts measuring 0.5-0.8 sm

with generally more than five microcysts in each ovary. As the number of microcysts increases and the ovarian volume enlarges, clinical and endocrine abnormalities become more obvious, and the condition becomes more severe. 3. What is the diagnosis? A lot of causes could be attributed to irregular menses. Stress, menopause, trauma, pregnancy are just to name a few. However in our patient, she also manifested hirsutism. Hirsustism is defined as the excessive growth of thick, dark hair in locations where hair growth in women is normally minimal or absent. Such male-pattern growth of terminal body hair usually occurs in androgenstimulated locations, such as the face, chest, and areolae. Oftentimes, hirsutism and hypertrichosis are used interchangeably. However, hypertrichosis is actually an excessive quantity of hair in a normal location. Hirsutism is usually caused by an increased sensitivity of the skin to androgens (testosterone and androstenedione) or increased production of these hormones. Androgen disorders (hyperandrogenism) affects between 5% to 10% of all women. HyFigure 1 The Ferriman-Gallwey model quantitates the extent of hair growth in nine key anatomic perandrogenism is increased levels of sites (seven of them are shown). Hair growth is graded using a scale from 0 (no terminal hair) to 4 male hormone production in women. The (maximal growth), for a maximum score of 36. A score of 8 or more indicates the presence of anmost commonly seen symptom is irregudrogen excess. lar menstrual cycles (as is the chief complaint of our patient). Now, it becomes necessary to enumerate the possible causes of hirsutism or more specifically, those disorders that will cause hyperandrogenism. Drug-induced. Those drugs that were mentioned above in question number 1 are all able to cause hirsutism. However, this should be ruled out for there was no history of drug intake.

Late-Onset Congenital Adrenal Hyperplasia, aka partial f orms of CAH. This is an inherited disorder which is related to a specific gene that encodes an enzyme that is important for the production of adrenal hormones. The late-onset is the mild form of CAH which is characterized by excessive blood levels of testosterone in which cortisol and aldosterone levels are normal. It presents with excessive hair growth and some of its clinical features are same with Polycystic Ovarian Syndrome. The fact that this disease is inherited makes it not the right diagnosis. Cushing Syndrome. is a noncongenital form of adrenal hyperplasia. It is characterized by an excess of Figure 2. Frida Kahlo - the famous Mexican painter was fond of her mustache and thick adrenal cortisol production. It can also eyebrows, and usually included them in self-portraits produce hirsutism however, other signs of hypercortisolemia is not present such as moon facies, buffalo hump etc. Androgen-producing adrenal tumors are a rarity. Less common causes of hirsutism. Anorexia nervosa (obviously not seen in our patient), acromegaly (was also not shown), hypothyroidism (absent as possibly shown in the PE). Ovarian neoplasms that could produce hirsutism are Luteoma of pregnancy, Arrhenoblastomas, Leydig cell tumors, Hilar cell tumors and Thecal cell tumors. This does not apply to our patient since these neoplasms are more common in postmenopausal than in premenopausal women. Polycystic Ovarian Syndrome. aka Stein–Leventhal syndrome. Women with PCOS have abnormalities in the metabolism of androgens and estrogen and in the control of androgen production. High serum concentrations of testosterone, androstenedione, and dehydroepiandrosterone sulfate (DHEA-S) are very much evident. It is also associated with peripheral insulin resistance and hyperinsulinemia, and obesity amplifies the degree of both abnormalities. Insulin resistance in PCOS can be secondary to a postbinding defect in insulin receptor signaling pathways, and elevated insulin levels may have gonadotropinaugmenting effects on ovarian function. The BMI of our patient was computed to be 29 which is considered to be Obese1 in the Asia-Pacific standards. Moreover, a family history of both parents having DM will only make the diagnosis closer to PCOS. Furthermore, a proposed mechanism for anovulation (irregular menses) and elevated androgen levels suggests that, under the increased stimulatory effect of LH secreted by the anterior pituitary, stimulation of the ovarian theca cells is increased. In turn, these cells increase the production of androgens (eg, testosterone, androstenedione). Because of a decreased level of follicle-stimulating hormone

(FSH) relative to LH, the ovarian granulosa cells cannot aromatize the androgens to estrogens, and this inability leads to decreased estrogen levels and consequent anovulation. Growth hormone (GH) and insulinlike growth factor-1 (IGF-1) may also augmenting effect on ovarian function. After presenting the probable causes of hirsutism (hyperandrogenism) and ruling them out, the most plausible diagnosis now would be Polycystic Ovarian Syndrome. All of the presenting symptoms were related to PCOS including the PE findings. Based on the modified concensus of the National Institutes of Health and Child Health and Human Development, the following are diagnostic criteria for PCOS. •

Major

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Minor

Chronic anovulation Hyperandrogenemia Clinical signs of hyperandrogenism Other etiologies excluded Insulin resistance Perimenarchal onset of hirsutism and obesity Elevated LH-to-FSH ratio Intermittent anovulation associated hyperandrogenemia (free testosterone, DHEAS)

with

In this schema, there are only two major criteria for the diagnosis of PCOS: anovulation and the presence of hyperandrogenism as established by clinical or laboratory means. 4. How should this patient be managed? The initial management should be correction of the patient’s condition (PCOS) and awareness of possible diabetes and cardiovascular complications is of paramount importance. Initially, weight reduction in obese patients is recommended because it reduces insulin, SHBG, and androgen levels, as well as restoration of ovulation either alone or combined with ovulationinducing drugs. We can advice nutritional program and lifestyle change that could correct her obesity. Patient should be told that the goal of therapy, due to the pathophysiology of hirsutism, is the arrest of the virilizing process, not

the removal of hair. Once terminal hair has been established in the area of sexual hair, withdrawal of the androgen will not affect the established hair pattern. Amelioration of a specific disease state will not rid one totally of the excess hair growth, but it will help to slow the rate of growth. The goal then primarily is targeted towards decreasing coarse hair growth. Oral contraceptives acts by decreasing ovarian androgen production and increasing SHBG resulting to a decreased free androgen concentration. Observable diminution of hair growth may be seen in 6-12 months. Antiandrogens like spironolactone competes with androgens at the androgen receptor level however dysfunctional uterine bleeding and limited diuresis are adverse side-effects. Flutamide is similar to spironolactone although liver function must be monitored with this drug and is associated with fewer side-effects than spironolactone. Cyproterone acetate usually in combination with ethinyl estradiol decreases circulating androgen and LH levels and by inducing androgen antagonism effects at peripheral level. GnRH agonist eliminates ovarian steroid production and estrogen-progestin therapy serves protection against osteoporosis. 5alpha-reductase inhibitor like Finasteride is well-tolerated when other treatments may not be used, although caution must be exercised with this drug for its teratogenic potential. Eflornithine hydrochloride on the other hand is a topical cream that may be used for facial hirsutism. Improvement may be seen in 4 to 8 weeks with twice daily application in the face and chin. A combination of hormonal suppression and supportive measures offers the best long-term results for hirsute patients. Also another means considered for PCOS is Metformin therapy. Because hyprerinsulinmia appears to play a role in PCOS-associated anovultaion, treatment with insulin sensitizers may shift the endocrine balance towards ovulation and pregnancy. Metformin given 500mg 3x a day has been seen to increase ovulation rates. This results in a drop of insulin levels and improves reproductive functions.

References:  Berek: Novak’s Gynecology 14th Edition, 2007

 Harrisons’s Principles of Internal Medicine 16th edition  Hirsutism: Pathogenesis and causes by HERBERT P. GOODHEART, MD  Hirsutism from the eMedicine website: http://www.emedicine.com/derm/topic472.htm  Polycystic Ovarian Syndrome from the Medicine.net website: http://www.medicinenet.com/polycystic_ovary/article.htm  Dermatologic Disease Database: Hirsutism: http://www.aocd.org/skin/dermatologic_diseases/hirsutism.html  Polycystic Ovarian Syndrome from the eMedicine website: http://www.emedicine.com/med/topic2173.htm  Irregular menstrual periods: Symptom Causes from the WrongDiagnosis website: http://www.wrongdiagnosis.com/symptom/irregular-menstrual-periods.htm