A 41 -year-old housewife was brought to the hospital by her husband because she had put on so much weight that she could no longer cope with her household chores. He was a well to do business man who appeared to care for his wife a great deal. He had employed a cook to help in the kitchen and a maid to help with the washing, ironing and sweeping of the floors. His wife was so tired that she did not get out of bed or walk around the house to even supervise the help. She was not drowsy but just very tired and found it difficult to get out of bed or get up from a chair. She could not climb stairs so the upper part of the house was neglected. She was depressed, did not want to meet people or go for walks and had put on 23 kg weight in 5 months. Her husband was genuinely concerned that she was ill and wanted her investigated. Her appetite was not noticeably increased.
They had 4 children ranging from 20 to 13 years of age. She had not practised any contraception and had not had any periods for 2 years. Her Gynaecologist had suggested early menopause as the cause of secondary infertility and amenorrhoea. As the couple had completed their family they did not investigate the matter further.
She weighed 92 kg and had a height of 5’1″. (The formula is BMI = kg/m2 where kg is a person’s weight in kilograms and m2 is their height in metres squared. A BMI of 25.0 or more is overweight, while the healthy range is 18.5 to 24.9.). Her BP was 145/100 on amlodipine 5mg per day, pulse was 76/min and respiration was 14/min. She had no wheezing or orthopnoea. She had excessive facial hair on her cheeks, upper lip and chin, which she removed unsuccessfully with a waxing process and covered with makeup. Her face was plump and rounded, with a heavy fat pad at the back of the neck and. Most of the obesity was truncal. Her thyroid gland was not visible because of the fat in her neck nor were the neck veins visible. On palpation the thyroid gland and cervical lymph nodes were not palpable. She appeared depressed with a slow response to questions but was aware of her problems and corrected her husband when he was confused about her treatment. She knew that she was not diabetic. It was winter in Karachi when she came to the hospital and she wore a shawl and cotton socks but no woollen cardigan or jacket.
Her lungs were clear and there was no cardiomegaly nor any added sounds in her heart. her abdomen was protuberant with an inverted umbilicus. There were large striae more so in the flanks which were purplish red. There were no petechiae or bruises anywhere else. Neither liver nor spleen or kidneys were palpable. There was no detectable shifting dullness or fluid thrill. She declined a rectal and vaginal examination saying that her gynecologist had seen her and told her there was nothing wrong. She had no pitting edema and and the joints were unremarkable.
What would you think about a 41 year old woman who is gaining weight? She appears to have Cushingoid features but let us analyse her findings.
Is weight the only method of checking obesity? In the Study of Women’s Health Across the Nation (SWAN), waist circumference and fat mass were measured with bioelectrical impedance pregnancy.
- Women tend to put on some weight after the menarche and then with the first pregnancy (about 11 to 16 kg). Weight tends to increase with each successive pregnancy. In this patient we have a history that her massive weight gain seems to be limited to 5 months.
- Although oral contraception has been anecdotally linked to obesity there is no supporting data.
- Menopause. Weight gain and changes in fat distribution often occur in the early postmenopausal years (usually initial 3 years). This appears to be caused by ovarian aging and general aging. In a three-year substudy of women in the Women’s Health Initiative (WHI), women who received estrogen and progesterone therapy lost significantly less lean soft tissue mass than did the women who received placebo. Estrogen therapy alone does not cause weight loss. This lady may be suffering from early ovarian failure but her weight gain does not appear to coincide with her period of amenorrhoea.
- Behavioral and physical inactivity and dietary habits. As children grow up and affluence sets in less activity is seen in everyday life among adults. Cars and public transport are available so people walk less. Food such as processed and unprocessed meat, potato chips, precooked snacks and the consumption of rich food as a form of entertainment all contribute to the ingestion and storage of excessive calories. Binge eating, night eating and snacking while watching TV all contribute to obesity.
- Hypothalamic obesity — Hypothalamic obesity is a rare syndrome in humans that can be regularly produced in animals by injury to the ventromedial or paraventricular region of the hypothalamus or the amygdala. The pathology may be trauma, tumor, inflammation or surgery.
- When taking the history ask about medication which may have caused the obesity. Medications which are a common cause of weight gain include insulin, sulfonylureas, thiazolidinediones, glucocorticoids, and antipsychotics.
- Cushing’s syndrome. A common clinical feature in patients with Cushing’s syndrome is progressive central (centripetal) obesity, usually involving the face, neck (leading to a buffalo hump and obscuring of the clavicles), trunk, abdomen, and, internally, the mesentery and mediastinum. The extremities are usually spared and are often wasted. This effect of glucocorticoids in Cushing’s syndrome can be explained by the induction of 11-beta-hydroxysteroid dehydrogenase type 1 in visceral fat, which enhances the lipogenic capacity of this tissue. ( Viva question: why do patients put on weight with administered steroids?).
- Hypothyroidism. Patients with hypothyroidism often gain weight due to slowing of metabolic activity. Some of this gain is fat. The weight gain is usually modest, and marked obesity is uncommon. Increasing serum thyroid-stimulating hormone (TSH) concentrations within the normal range have also been associated with a modest increase in body weight in adults, but treatment of subclinical hypothyroidism does not appear to be associated with weight loss. Bad luck!! Do not prescribe thyroxine in order to reduce weight. You will only suppress the thyroid.
- Polycystic ovary syndrome. Approximately 50 percent of women with polycystic ovary syndrome (PCOS) are obese, but PCOS itself does not cause obesity. PCOS can also cause androgen excess and may cause hirsutism in women. Remember that women with PCOS are resistant to insulin. Reducing the degree of insulin resistance and hyperinsulinemia with weight loss, metformin, or a thiazolidinedione, is associated with decreased androgen levels in women with PCOS.Questions you need to ask during the history taking: did she take several years to conceive? Did she require therapy with clomiphene citrate to help conceive? Did she experience miscarriages or lost pregnancies? Question in the viva: if you are investigating androgenization in this lady what biochemistry will you check? Total testosterone, free testosterone, and DHEAS concentrations. Why is metformin prescribed for PCOS?
- Growth hormone deficiency. Growth hormone deficiency in adults is associated with an increase in abdominal and visceral fat.
Women seek medical help when coarse, terminal hair begins to grow on areas which are sensitive to androgens i,e, upper lips, cheeks, chin, chest, upper abdomen. This is often associated with PCOS. Recent onset of hirsutism i.e. less than a year (as in this lady) or sudden increase in the hair growth indicates the presence of an androgen secreting tumor. If a woman is already taking oral contraceptives measuring the androgen levels is not of diagnostic value. Look for other evidence of virilization: deepening of the voice, cliteromegaly and increase in muscle mass.
Common causes of hirsutism include PCOS in which there is peripubertal onset of symptoms, oligomenorrhea, obesity, polycystic ovaries on ultrasound and
nonclassic 21-hydroxylase deficiency.
Uncommon causes include: Classic 21-hydroxylase deficiency (Diagnosed during infancy, ambiguous genitalia.)
Androgen-secreting ovarian tumors (Sertoli-Leydig cell, granulosa-theca cell, hilus cell) This has an onset in the third decade later (usually postmenopausal), rapidly progressive hirsutism, virilization.
Androgen-secreting adrenal tumors. Some women with adrenocortical cancer present with just virilization, but a mixed Cushing’s and virilization syndrome is more common.
Ovarian hyperthecosis: onset in third decade or later (usually postmenopausal), rapidly progressive hirsutism, virilization. There is severe insulin-resistance.
Cushing’s disease. Corticotroph adenoma secreting ACTH results in excess cortisol and adrenal androgens.
Drugs Use of exogenous androgens (testosterone or DHEA) can cause hirsutism and acne as in illicit use in athletes and sports women.
Acromegaly Enlarged jaw (macrognathia) and enlarged, swollen hands and feet, which result in increasing shoe, glove, and ring sizes. Patients with large pituitary tumors may have headaches, visual field defects, and cranial nerve palsies.
In the differential diagnosis of this lady we need to consider an adrenal tumour benign or malignant, adenoma of the pituitary gland secreting corticotropin, an androgen secreting tumour of the ovaries.
These are stretch marks on the skin representing skin scars caused by distension. They are initially an angry red (striae rubra) and later become depigmented or striae alba. Striae rubra are the earliest presentation of striae distensae and are characterized by an erythematous to violaceous color. Over time, striae rubra evolve into striae alba, which appear hypopigmented, atrophic, and scar-like. Common locations for striae distensae are the abdomen, breasts, medial upper arms, hips, lower back, buttocks, and thigh. The incidence is 11% of normal men and 85% of pregnant women.
Patients with Cushing’s syndrome may have particularly prominent and widely distributed striae. Striae distensae secondary to topical corticosteroid use often occur in intertriginous areas.
The histopathologic findings of striae rubra and striae alba differ. Striae rubra exhibit flattening of the epidermis with loss of rete ridges. An inflammatory infiltrate with lymphocytes and histiocytes may be present in the dermis. The centers of early striae rubra may also show a reduction in normal collagen, elastin, and fibrillin content in the dermis while thick, tortuous elastic fibers reside at the periphery. Pathologic analysis of early, erythematous striae gravidarum reveals disorganized collagen fibrils that fail to form normal collagen bundles.
Electron microscopy may demonstrate mast cell degranulation, macrophage activation, and elastolysis in the mid-dermis.
Striae alba exhibit histopathology similar to that of an atrophic scar, with epidermal atrophy, loss of rete ridges, and thin dermal collagen bundles arranged parallel to the skin surface.
This lady had an abdominal surgical scar. She had had an adrenal tumor (benign) removed from her right adrenal gland. She was beginning to lose the evidence of Cushing’s syndrome and had lost some weight, she had declined oral contraceptives.