Demam

Demam bukan merupakan suatu penyakit, tetapi hanyalah merupakan gejala dari suatu penyakit. Suhu tubuh normal adalah 370C. Apabila suhu tubuh lebih dari 37,20C pada pagi hari dan lebih dari 37,70C pada sore hari berarti demam. Kenaikan suhu 380C pada anak di bawah lima tahun dapat menimbulkan kejang dengan gejala antara lain: tangan dan kaki kejang, mata melihat ke atas, gigi dan mulut tertutup rapat, serta penurunan kesadaran. Keadaan demikian segera ke dokter.

Penyebab
Demam umumnya disebabkan oleh infeksi dan non infeksi. Penyebab infeksi antara lain kuman, virus, parasit, atau mikroorganisme lain. Contoh : radang tenggorokan, cacar air, campak, dan lain-lain. Penyebab non infeksi antara lain dehidrasi pada anak dan lansia, alergi, stres, trauma, dan lain-lain.
Gejala-gejala
- Kepala, leher dan tubuh akan terasa panas, sedang tangan dan kaki dingin
- Mungkin merasa kedinginan dan menggigil bila suhu meningkat dengan cepat
Hal Yang Dapat Dilakukan
- Istirahat yang cukup.
- Minum air yang banyak.
- Usahakan makan seperti biasa, meskipun nafsu makan berkurang .
- Periksa suhu tubuh setiap 4 jam.
- Kompres dengan air hangat
- Hubungi dokter bila suhu sangat tinggi (diatas 380C), terutama pada anak-anak.
Petunjuk penggunaan termometer :
- Kocok termometer sebelum mengukur sampai air raksa turun di bawah tanda 350C
- Termometer ditaruh di bawah lidah selama 1 menit atau di bawah lipatan lengan (ketiak) selama 4 menit pada orang dewasa dan anak-anak. Suhu normal di bawah lipatan lengan (ketiak) adalah 36,50C. Untuk mendapatkan suhu yang setara dengan suhu mulut, tambahkan 0,50C pada suhu yang terbaca.
- Cuci termometer sebelum dan sesudah dipakai.
Kapan harus ke dokter
- Bila seorang bayi menderita panas
- Bila demam lebih dari 390C (pada anak-anak 38,50C) dan tidak bisa turun dengan parasetamol atau kompres.
- Bila demam tidak berkurang setelah 2 hari
- Bila demam disertai dengan kaku leher
- Bila disertai gejala-gejala lain yang berkaitan dengan demam seperti : ruam kulit, sakit tenggorokan berat, batuk dengan dahak berwarna hijau, sakit telinga, sakit perut, diare, sakit bila buang air kecil atau terlalu sering buang air kecil, bintik-bintik merah pada kulit, kejang, pingsan
- Bila terjadi demam setelah melahirkan atau keguguran

Obat Yang Dapat Digunakan
Obat yang dapat digunakan untuk mengatasi keluhan demam yaitu:
1. Parasetamol/Asetaminofen
a. Kegunaan obat
Menurunkan demam, mengurangi rasa sakit
b. Hal yang harus diperhatikan
 Dosis harus tepat, tidak berlebihan, bila dosis berlebihan dapat menimbulkan gangguan fungsi hati dan ginjal.
 Sebaiknya diminum setelah makan
 Hindari penggunaan campuran obat demam lain karena dapat menimbulkan overdosis.
 Hindari penggunaan bersama dengan alkohol karena meningkatkan risiko gangguan fungsi hati.
 Konsultasikan ke dokter atau Apoteker untuk penderita gagal ginjal.
c. Kontra Indikasi
Obat demam tidak boleh digunakan pada :
• penderita gangguan fungsi hati
• penderita yang alergi terhadap obat ini
• pecandu alkohol
d. Bentuk sediaan
Tablet 100 mg
Tablet 500 mg
Sirup 120 mg/5ml
e. Aturan pemakaian
Dewasa : 1 tablet (500 mg) 3 – 4 kali sehari, (setiap 4 – 6 jam)
Anak :
• 0 – 1 tahun : ½ - 1 sendok teh sirup, 3–4 kali sehari (setiap 4 – 6 jam)
• 1 – 5 tahun : 1 – 1 ½ sendok teh sirup, 3 – 4 kali sehari (setiap 4 – 6 jam)
• 6-12 tahun : ½ - 1 tablet (250-500 mg), 3 – 4 kali sehari (setiap 4 – 6 jam)


2. Asetosal (Aspirin)
a. Kegunaan obat
Mengurangi rasa sakit, menurunkan demam, antiradang
b. Hal yang harus diperhatikan
- Aturan pemakaian harus tepat, diminum setelah makan atau bersama makanan untuk mencegah nyeri dan perdarahan lambung.
- Konsultasikan ke dokter atau Apoteker bagi penderita gangguan fungsi ginjal atau hati, ibu hamil, ibu menyusui dan dehidrasi
- Jangan diminum bersama dengan minuman beralkohol karena dapat meningkatkan risiko perdarahan lambung.
- Konsultasikan ke dokter atau Apoteker bagi penderita yang menggunakan obat hipoglikemik, metotreksat, urikosurik, heparin, kumarin, antikoagulan, kortikosteroid, fluprofen, penisilin dan vitamin C.
c. Kontra Indikasi
Tidak boleh digunakan pada:
- Penderita alergi termasuk asma
- Tukak lambung (maag) dan sering perdarahan di bawah kulit
- Penderita hemofilia dan trombositopenia
d. Efek samping
- Nyeri lambung, mual, muntah
- Pemakaian dalam waktu lama dapat menimbulkan tukak dan perdarahan lambung
e. Bentuk Sediaan
Tablet 100 mg
Tablet 500 mg
f. Aturan pemakaian
Dewasa : 500 mg setiap 4 jam (maksimal selama 4 hari)
Anak : 2 – 3 tahun : ½ - 1 ½ tablet 100 mg, setiap 4 jam
4 – 5 tahun : 1 ½ - 2 tablet 100 mg, setiap 4 jam
6 – 8 tahun : ½ - ¾ tablet 500 mg, setiap 4 jam
9 – 11 tahun : ¾ - 1 tablet 500 mg, setiap 4 jam
> 11 tahun : 1 tablet 500 mg, setiap 4 jam

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Selesma & Influenza

Selesma, atau disebut juga commond cold atau rhinitis adalah iritasi atau peradangan dari selaput lendir hidung akibat masuk angin dan atau infeksi dengan suatu virus atau bakteri. Selaput lendir yang meradang memproduksi lebih banyak lendir dan mengembang, sehingga hidung menjadi tersumbat dan pernafasan amat dipersulit. Lendir yang terbentuk dapat mengakibatkan batuk dan bersin.
Penyebab selesma dan influenza

Selesma dapat disebabkan oleh adanya rhinovirus (rhino = hidung), ditandai dengan lendir (ingus) yang encer dan bening. Pada tingkat kedua baru dapat terjadi supra-infeksi oleh suatu bakteri, yang biasanya sudah berada dalam mulut atau hidung dan mendadak menjadi patogen (menimbulkan penyakit). Selesma yang disebabkan oleh bakteri ditandai dengan lendir (ingus) yang kental dan berwarna kuning kehijauan. Penyebab lain dari selesma adalah suatu reaksi alergi dari tubuh terhadap suatu zat yang dapat menimbulkan reaksi kepekaan berlebihan. Zat-zat alergen antara lain yaitu serbuk sari dari pohon, bunga atau jenis rumput-rumputan. Begitupula debu rumah tangga yang mengandung suatu serangga kecil tertentu (tungau) yang tidak dapat dilihat dengan mata telanjang. Selesma demikian disebut rhinitis alergi. Ciri-cirinya yang khas adalah ingus yang sangat encer, kelopak mata dan hidung bengkak dan gatal. Penurun kelembaban dan suhu udara oleh mesin airconditioner (AC) dapat mengiritasi mukosa hidung sehingga menimbulkan selesma. Begitu juga menghisap rokok melalui hidung atau adanya udara yang terpolusi.
Influenza hampir sama dengan selesma, tetapi umumnya bersifat lebih berat. Penyebab influenza adalah beberapa virus influenza A, B, dan C yang terdiri dari banyak suku. Virus yang bersifat sangat menular cenderung menyerang saluran pernafasan dan dapat menimbulkan radang bronki (bronkitis) dan radang paru-paru. Ciri-ciri infeksi adalah demam tinggi, nyeri otot dan persendian dengan rasa letih, nyeri kepala dan tenggorokan, suara serak, hilang nafsu makan, adakalanya juga nyeri telinga, mual, muntah dan diare.
Gejala selesma dan influenza
Perbedaan gejala selesma dan influenza :
Gejala Selesma Gejala Influenza
Jarang atau demam ringan Demam tinggi
Kadang-kadang sakit kepala Selalu sakit kepala
Hidung kotor, berlendir Hidung bersih
Hidung tersumbat Kadang-kadang hidung tersumbat
Batuk ringan Batuk lebih berat
Terkadang bterasa sakit Sering terasa sakit
Sedikit lelah Kelalahan beberapa minggu
Radang tenggorokan Kadang radang tenggorokan

Infeksi dengan virus terutama terjadi melalui udara yang mengandung tetesan ludah, lendir atau ingus yang berasal dari seseorang pasien yang berbicara, batuk atau bersin, juga melalui sendok garpu atau gelas minuman, ataupun melalui tangan, dsb. Dengan demikian penularan penyakit dapat menyebar dengan mudah dan pesat sekali.
Tubuh yang sehat memiliki daya tangkis alami yang cukup kuat untuk melindunginya terhadap bermacam-macam penyakit, juga terhadap serangan berbagai virus. Akan tetapi, bila sistem tangkis tubuh akibat suatu sebab menurun, maka virus dapat menerobos dan menginvasi ke dalam sel-sel tubuh. Pertama-tama diserang mucosa dari hidung, leher, dan saluran nafas (bronki dan paru-paru), dimana bulu-bulu getar dirusak. Keadaan ini timbul bila kondisi tubuh buruk, misalnya setelah menderita penyakit serius, akibat kerja fisik terlalu berat dan terlampau letih, stres atau tidak cukup makan bergizi. Daya tangkis juga menurun bila suhu tubuh menurun di bawah 370 C, misalnya bila berjalan-jalan dengan baju basah setelah olahraga atau masuk angin.
Pengobatan selesma dan influenza
Untuk mencegah infeksi yang disebabkan karena virus selesma atau influenza hingá kini belum ditemukan obatnya, yaitu obat yang berkhasiat mematikan semua virus tersebut. Hanya gejala-gejala seperti pilek, nyeri kepala, otot dan sendi, demam, batuk, dan sebagainya dapat disembuhkan dengan obat untuk meringankan penyakit. Dengan istirahat total lebih kurang selama 5 hari, pada umumnya gangguan-gangguan tersebut sembuh dengan sendirinya.
1. Terapi dengan obat
Obat-obat selesma biasanya mengandung antihistamin dan dekongestan. Antihistamin adalah suatu kelompok obat yang dapat berkompetisi melawan histamin, yaitu salah satu mediator dalam tubuh yang dilepas pada saat terjadi reaksi alergi. Obat yang tergolong antihistamin antara lain : klorfeniramin maleat (CTM), difenhidramin HCl, promethazin. Hal yang perlu diperhatikan dalam penggunaan obat-obat antihistamin yaitu : hindari dosis melebihi yang dianjurkan, hindari penggunaan bersama minuman beralkohol atau obat tidur, penderitaq gloukoma atau retensi urine akibat hipertrofi prostat apabila menggunakan obat yang mengandung antihistamin agar dikonsultasikan dahulu dengan dokter, jangan minum obat antihistamin bila akan mengemudikan kendaraan dan menjalankan mesin. Efek samping yang mungkin timbul yaitu : mengantuk, pusing, gangguan sekresi saluran nafas, mual dan jarang terjadi muntah. Aturan pemakaiaan :
• Klorfeniramin maleat (CTM) untuk dewasa 1 tablet (2 mg) setiap 6-8 jam, untuk anak kurang dari 12 tahun ½ tablet setiap 6-8 jam.
• Difenhidamin HCl untuk dewasa 1-2 kapsul (25-50 mg) setiap 8 jam, untuk anak ½ tablet (12,5 mg) setiap 6-8 jam.
• Promethazin untuk dewasa 50-300 mg sehari, untuk anak usia 1-5 tahun 5-15 mg sehari, usia 5-10 tahun 10-25 mg setiap hari.
Dekongestan adalah obat yang mempunyai efek mengurangi hidung tersumbat. Berdasarkan cara pemberiannya dapat dibedakan antara dekongestan oral (melalui mulut) dan dekongestan topikal (diteteskan ke dalam hidung). Obat dekongestan oral antara lain : fenilpropanolamin, fenilefrin, pseudoefedrin, efedrin. Hal yang harus diperhatikan dalam penggunaan obat dekongestan oral adalah hati-hati pada penderita diabet juvenil karena dapat meningkatkan kadar gula darah, penderita tiroid, hipertensi, gangguan jantung, dan penderita yang menggunakan obat antidepresi. Efek samping yang mungkin timbul dari penggunaan obat dekongestan oral yaitu : menaikkan tekanan darah, aritmia terutama pada penderita penyakit jantung dan pembuluh darah. Aturan pemakaiaan :
• Fenipropanolamin untuk dewasa maksimal 15 mg per takaran 3-4 kali sehari, untuk anak 6-12 tahun maksimal 7,5 mg per takaran 3-4 kali sehari.
• Fenilefrin untuk dewasa 10 mg 3 kali sehari, untuk anak 6-12 tahun 5 mg 3 kali sehari.
• Pseudoefedrin untuk dewasa 60 mg 3-4 kali sehari, untuk anak 2-5 tahun 15 mg 3-4 kali sehari, untuk anak 6-12 tahun 30 mg 3-4 kali sehari.
• Efedrin untuk dewasa 25-30 mg setiap 3-4 jam, untuk anak sehari 3 mg/kg berat bada dibagi dalam 4-6 dosis yang sama.
Termasuk dekongestan topikal adalah oksimetazolin. Hal yang perlu diperhatikan dalam penggunaan obat tersebut yaitu : hindari dosais melebihi yang dianjurkan, hati-hati sewaktu meneteskan ke hidung, dosis tepat dan masuknya ke lubang hidung harus tepat, jangan mengalir ke luar atau tertahan, tidak boleh digunakan lebih dari 7-10 hari, segera minum setelah menggunakan obat, karena air dapat mengencerkan obat yang tertelan, ujung botol obat dibilas dengan air panas setiap kali dipakai, penggunaan obat pada pagi dan menjelang tidur malam, dan tidak boleh digunakan lebih dari 2 kali dalam 24 jam. Obat tidak boleh digunakan untuk anak berumur dibawah 6 tahun, karena efek samping yang timbul lebih parah, dan ibu hamil muda. Efek samping obat ini yaitu : merusak mukosa hidung karena hidung tersumbat makin parah, rasa terbakar, kering, bersin, sakit kepala, sukar tidur, berdebar Aturan pemakaian :
• Oksimetazolin untuk dewasa dan anak di atas 6 tahun 2-3 tetes/semprot oksimetazolin 0,005% setiap lubang hidung, untuk anak usia 2-5 tahun 2-3 tetes/semprot oksimetazolin 0,025% setiap lubang hidung, untuk anak kurang dari 2 tahun ikuti petunjuk dokter.
Pada umumnya obat influenza mengandung antara lain : antihistamin, dekongestan, analgetik/antipiretik, ekspektoran, antitusif. Analgetik/antipiretik adalah obat yang digunakan untuk menghilangkan nyeri dan menurunkan demam. Obat yang termasuk analgetik/antipiretik yang dapat dibeli bebas yaitu : parasetamol (asetaminofen) dan aspirin (asetosal). Hal yang perlu diperhatikan dalam penggunaan parasetamol yaitu : dosis harus tepat, bila dosis berlebihan dapat menimbulkan gangguan fungsi hati dan ginjal, sebiknya diminum setelah makan, hindari penggunaan campuran obat demam lain karena dapat menimbulkan over dosis, hindari penggunaan bersama dengan alkohol karena dapat meningkatkan resiko gangguan fungsi hati, bila diminum dengan kopi atau minuman lain yang mengandung kofein dapat memperkuat efek obat. Parasetamol tidak boleh digunakan pada penderita gangguan fungsi hati, penderita yang alergi terhadap obat ini, dan pecandu alkohol. Aturan pemakaian :
• Parasetamol untuk dewasa 1 tablet (500 mg) setiap 4-6 jam, untuk anak usia 0-1 tahun ½-1 sendok teh sirup setiap 4-6 jam, untuk anak usia 1-5 tahun 1-1½ sendok teh sirup setiap 4-6 jam, untuk anak usia 6-12 tahun ½-1 tablet (250-500 mg) setiap 4-6 jam. Beberapa obat paten yang mengandung parasetamol antara lain : biogesic, bodrex, farmadol, panadol, sanmol, dll.
Asetosal berkhasiat mengurangi rasa nyeri, menurunkan demam, dan antiradang. Hal yang perlu diperhatikan dalam penggunaan asetosal yaitu : aturan pemakaian harus tepat, diminum setelah makan atau bersama makan untuk mencegah nyeri dan perdarahan lambung, jangan diminum bersama minuman beralkohol karena dapat meningkatkan resiko perdarahan lambung, anak-anak dengan selesama atau influenza tidak dianjurkan menggunakan obat ini karena dapat menimbulkan sejenis radang otak (rye sindrom), begitu pula wanita hamil dan menyusui sebaiknya tidak menggunakan obat ini. Efek samping yang mungkin terjadi pada penggunaan asetosal yaitu : nyeri lambung, mual muntah, pemakaian dalam waktu lama dapat menimbulkan tukak dan perdarahan lambung. Asetosal tidak boleh digunakan pada penderita alergi, asma, tukak lambung (maag), penderita hemofili dan trombositopenia. Aturan pemakaian :
• Asetosal untuk dewasa 1 tablet (500 mg) setiap 4 jam maksimal selama 4 hari, untuk anak usia 2-3 tahun ½-1½ tablet 100 mg setiap 4 jam, untuk anak usia 4-5 tahun 1 ½-2 tablet 100 mg setiap 4 jam, untuk anak usia 6-8 tahun ½-3/4 tablet 500 mg setiap 4 jam. Beberapa obat paten yang mengandung asetosal antara lain : aspirin, bodrexin, farmasal, naspro, dll.
Ekspektoran/antitusif adalah obat yang digunakan untuk mengatasi batuk berdahak/batuk kering yang menyertai gejala selesma atau influenza. Akan lebih banyak diulas pada pembahasan tentang batuk.
2. Terapi dengan obat tradisional
• Seduhan hangat 1 rimpang jahe, kencur, dan 5 biji cengkeh sekali sehari selama 3 hari.
• Seduhan hangat 1 rimapang jahe, 3 lembar daun sirih, dan 3 biji cengkeh sekali sehari selama 3 hari.
• Madu dan jus buah-buahan dapat meningkatkan daya tahan tubuh.
• Banyak minum teh, sari buah, dan menghisap cengkeh akan mengurangi rasa kering serta mengencerkan dahak di tenggorokan.

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Polycystic Ovary Syndrome... Treatment with Insulin Lowering Medications

INTRODUCTION:
Polycystic ovary syndrome is characterized by anovulation (irregular or absent menstrual periods) and hyperandrogenism (elevated serum testosterone and androstenedione). Patients with this syndrome may complain of abnormal bleeding, infertility, obesity, excess hair growth, hair loss and acne. In addition to the clinical and hormonal changes associated with this condition, vaginal ultrasound shows enlarged ovaries with an increased number of small (6-10mm) follicles around the periphery (Polycystic Appearing Ovaries or PAO). While ultrasound reveals that polycystic appearing ovaries are commonly seen in up to 20% of women in the reproductive age range, PolyCystic Ovary Syndrome (PCOS) is a estimated to affect about half as many or approximately 6-10% of women.

The condition appears to have a genetic component and those effected often have both male and female relatives with adult-onset diabetes, obesity, elevated blood triglycerides, high blood pressure and female relatives with infertility, hirsutism and menstrual problems.

HYPERINSULIN & PCOS?
As of yet, we do not understand why one woman who demonstrates polycystic appearing ovaries on ultrasound has regular menstrual cycles and no signs of excess androgens while another develops PCOS. One of the major biochemical features of polycystic ovary syndrome is insulin resistance accompanied by compensatory hyperinsulinemia (elevated fasting blood insulin levels). There is increasing data that hyperinsulinemia produces the hyperandrogenism of polycystic ovary syndrome by increasing ovarian androgen production, particularly testosterone and by decreasing the serum sex hormone binding globulin concentration. The high levels of androgenic hormones interfere with the pituitary ovarian axis, leading to increased LH levels, anovulation, amenorrhea, recurrent pregnancy loss, and infertility. Hyperinsulinemia has also been associated high blood pressure and increased clot formation and appears to be a major risk factor for the development of heart disease, stroke and type II diabetes.

DIAGNOSIS
There is little agreement when it comes to how PCOS is diagnosed. Most physicians will consider this diagnosis after making sure you do not have other conditions such as Cushing's disease (overactive adrenal gland), thyroid problems, congenital adrenal hyperplasia or increased prolactin production by the pituitary gland. TSH, 17-hydroxyprogesterone, prolactin and a dexamethasone suppression test may be advisable. After reviewing your medical history, your physicians will determine which tests are necessary. If you have irregular or absent menstrual periods, clues from the physical exam will be considered next. Your height and weight will be noted along with any increase facial or body hair or loss of scalp hair, acne and acanthosis nigricans (a discoloration of the skin under the arms, breasts and in the groin). Elevated androgen levels (male hormones), DHEAS or testosterone help make the diagnosis. A two hour insulin and glucose tolerance test will be obtained. Many physicians tell their patients that insulin values are normal, when in fact the value indicates that insulin may be playing a role in stimulating the development of PCOS. Most labs report levels less than 25-30 miu/ml as normal, while in fact, levels over 10miu/ml on a fasting blood sample suggests that PCOS may be related to hyperinsulinism. As women with polycystic ovary syndrome may be a greater risk for other medical conditions, testing for cardiovascular risk factors such as blood lipids, homocysteine, CRP and PAI-1 (a blood factor that promotes abnormal clotting) will also be carried out.

NEWER METHODS OF TREATMENT
Traditional treatments have been difficult, expensive and have limited success when used alone. Infertility treatments include weight loss diets, ovulation medications (clomiphene,letrozole, Follistim, Gonal-F), ovarian drilling surgery and IVF. Other symptoms have been managed by anti-androgen medication (birth control pills, spironolactone, flutamide or finasteride).

Ovarian drilling can be performed at the time of laparoscopy. A laser fibre or electrosurgical needle is used to puncture the ovary 10-12 times. This treatment results in a dramatic lowering of male hormones within days. Studies have shown that up to 80% will benefit from such treatment. Many who failed to ovulate with letrozole or metformin therapy will respond when rechallenged with these medications after ovarian drilling. Interestingly, women in these studies who are smokers, rarely responded to the drilling procedure. Side effects are rare, but may result in adhesion formation or ovarian failure if the procedure is performed by an inexperienced surgeon.

For women in the reproductive age range, polycystic ovary syndrome is a serious, common cause of infertility, because of the endocrine abnormalities which accompany elevated insulin levels. There is increasing evidence that this endocrine abnormality can be reversed by treatment with widely available standard medications which are leading medicines used in this country for the treatment of adult onset diabetes, metformin (Glucophage 500 or 850 mg three times per day or 1000mg twice daily with meals), pioglitazone (Actos 15-30 mg once a day), rosiglitazone (Avandia 4-8 mg once daily) or a combination of these medications. These medications have been shown to reverse the endocrine abnormalities seen with polycystic ovary syndrome within two or three months. They can result in decreased hair loss, diminished facial and body hair growth, normalization of elevated blood pressure, regulation or menses, weight loss, reduction in cardiovascular risk factors, normal fertility, and a reduced risk of miscarriage. We have seen pregnancies result in less than two months in woman who conceived in their very first ovulatory menstrual cycle. By six months over 90% of women treated with insulin-lowering agents, diet and exercise will resume regular menses.

The medical literature suggests that the endocrinopathy in most patients with polycystic ovary syndrome can be resolved with insulin lowering therapy. This is clinically very important because the therapy reduces hirsutism, obesity, blood pressure, triglyceride levels, elevated blood clotting factors and facilitates reestablishment of the normal pituitary ovarian cycle, thus often allowing resumption of normal ovulatory cycles and pregnancy. We know the polycystic ovary syndrome is associated with increased risk of heart attack and stroke because of the associated heart attack and stroke risk factors, hypertension, obesity, hyperandrogenism, hypertriglyceridemia, and these are to a large degree resolved by therapy with these medications.

ARE THESE MEDICATIONS SAFE?
Side effects are rare. Although metformin, rosiglitazone and pioglitazone lower elevated blood sugar levels in diabetics, when given to nondiabetic patients, they only lower insulin levels. Blood sugar levels will not change. In fact, episodes of "hypoglycemic attacks" appear to be reduced.

METFORMIN (Glucophage):
When first starting this medication, people will often experience upset stomach or diarrhea which usually resolves after the first week. This side effect can be minimized by taking metformin with a meal and starting with a low dose. I recommend that our patients start with one 500 mg pill daily the first week and increase to twice a day during the second week. If after the second week GI side effects are minimal, the dose is increased to 850 mg twice daily. Surprisingly, we have found that the extended release version, Glucophage XR seems to be associated with less weight loss as compared to the generic preparation. Patients with reduced renal function (creatinine >1.5 or creatinine clearance <60%)>30%) risk of miscarriage. Dr. Glueck notes similar increased risk of miscarriage following metformin therapy. He notes that the risk of miscarriage is increased in those patients with a prior history of miscarriage, those with high LH, high androgen levels, hyperinsulinemia or elevated PAI-Fx. Initial findings in a non-ramdomized trial suggest a decreased risk of miscarriage if metformin is continued throughout the pregnancy. At present there is insufficient data to routinely advise continuation of metformin during pregnancy. As an alternative to continuing metformin therapy, those women with increased risk of abnormal blood clotting may benefit from baby aspirin, folate supplementation and low dose heparin therapy. Pregnancy loss is a troubling concern. This information is provided to enable you work with your ob/gyn physician to make an informed decision about your care.

BIBLIOGRAPHY
1. Velazquez EM, Mendosa S, Hamer T, Sosa F, Glucck CJ. Metformin therapy in women with polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating menstrual regularity and pregnancy. Metabolism 1994,43:647­655.

2. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450cl7alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. New England J Medicine 1996,335:617­623.

3. Utiger RD. Insulin and the polycystic ovary syndrome. New England J Medicine 1996,335:657­658

4. Dunaif A, Scott D, Finegood D, Quintana ma B, Whitcomb R. The insulin sensitizing agent Troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome Endocrinol Metab 1996;81:3299­3306

5. Coetzee EJ, Jackson WP. The management of non-insulin-dependent diabets during pregnancy. Diabetes Res Clin Pract 1985-86;1:281-287

6. Homburg R. Polycystic ovary syndrome: induction of ovulation. Ballieres Cllinical Endocrinologys & Metabolism 1996; 10:281-292

7. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with polycystic ovary syndrome. Metabolism 1999; 48:1-10.

8. Tulppala M, Stenman UH, Cacciatore B, Ylikorkala O. Polycystic ovaries and levels of gonadotropins and androgens in recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum Reprod 1994;9:1328-32.

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Male Infertility Overview Assessment, Diagnosis, and Treatment

Stephen F. Shaban, M.D. Clinical Assistant Professor
Department of Surgery, Division of Urology
University of North Carolina School of Medicine

Chapel Hill, NC.

ASSESSMENT

Male Infertility --- Overview

Approximately 15% of couples attempting their first pregnancy meet with failure. Most authorities define these patients as primarily infertile if they have been unable to achieve a pregnancy after one year of unprotected intercourse. Conception normally is achieved within twelve months in 80-85% of couples who use no contraceptive measures, and persons presenting after this time should therefore be regarded as possibly infertile and should be evaluated. Data available over the past twenty years reveal that in approximately 30% of cases pathology is found in the man alone, and in another 20% both the man and woman are abnormal. Therefore, the male factor is at least partly responsible in about 50% of infertile couples.

Important issues related to the evaluation of the male factor include the most appropriate time for the male evaluation, the most efficient format for a comprehensive male exam, and definition of rationale and effective medical and surgical regimens in the treatment of these disorders. It is extremely important in the evaluation of infertility to consider the couple as a unit in evaluation and treatment and to proceed in a parallel investigative manner until a problem is uncovered. It has been shown that the longer a couple remains subfertile, the worse their chance for an effective cure. Many couples experience significant apprehension and anxiety after only a few months of failure to conceive. Unduly prolonged unprotected intercourse should not be advocated before a workup of the man is instituted. Initial screening of the man should be considered whenever the patient presents with the chief complaint of infertility. This initial evaluation should be rapid, non-invasive and cost effective. Of interest is the fact that pregnancy rates of up to 50% have been reported when only the woman has been investigated and treated even when the man was found to have moderately severe abnormalities of semen quality.

MALE REPRODUCTIVE PHYSIOLOGY

The Hypothalamic-Pituitary-Gonadal Axis

The hypothalamus is the integrative center of the reproductive axis and receives messages from both the central nervous system and the testes to regulate the production and secretion of gonadotropin releasing hormone (GnRH). Neurotransmitters and neuropeptides have both inhibitory and stipulatory influence on the hypothalamus. The hypothalamus releases GnRH in a pulsatile nature which appears to be essential for stimulating the production and release of both luteinizing hormone (LH) and follicle stimulating hormone (FSH). Interestingly and paradoxically, after the initial stimulation of these gonadotropins, the exposure to constant GnRH results in inhibition of their release. LH and FSH are produced in the anterior pituitary and are secreted episodically in response to the pulsatile release of GnRH. LH and FSH both bind to specific receptors on the Leydig cells and Sertoli cells within the testis. Testosterone, the major secretory product of the testes, is a primary inhibitor of LH secretion in males. Testosterone may be metabolized in peripheral tissue to the potent androgen dihydrotestosterone or the potent estrogen estradiol. These androgens and estrogens act independently to modulate LH secretion. The mechanism of feedback control of FSH is regulated by a Sertoli cell product called inhibin. Decreases in spermatogenesis are accompanied by decreased production of inhibin and this reduction in negative feedback is associated with reciprocal elevation of FSH levels. Isolated increased levels of FSH constitute an important, sensitive marker of the state of the germinal epithelium.

Prolactin also has a complex inter-relationship with the gonadotropins, LH and FSH. In males with hyperprolactinemia, the prolactin tends to inhibit the production of GnRH. Besides inhibiting LH secretion and testosterone production, elevated prolactin levels may have a direct effect on the central nervous system. In individuals with elevated prolactin levels who are given testosterone, libido and sexual function do not return to normal as long as the prolactin levels are elevated.

The Testes

Leydig; Cells

Testosterone is secreted episodically from the Leydig cells in response to LH pulses and has a diurnal pattern, with the peak level in the early morning and the trough level in the late afternoon or early evening. In the intact testis, LH receptors decrease or down-regulate after exogenous LH administration. Large doses of GnRH or its analogs can reduce the numbers of LH receptors and therefore inhibit LH secretion. This has been applied clinically to cause medical castration in men with prostate cancer. Estrogen inhibits some enzymes in the testosterone synthetic pathway and therefore directly effects testosterone production. There also appears to be an intratesticular ultra short loop feedback such that exogenous testosterone will override the effect of LH and inhibit testosterone production. In normal males, only 2% of testosterone is free or unbound. 44% is bound to testosterone-estradiol-binding globulin or TeBG, also called sex hormone-binding globulin. 54% of testosterone is bound to albumin and other proteins. These steroid-binding proteins modulate androgen action. TeBG has a higher affinity for testosterone than for estradiol, and changes in TeBG alter or amplify the hormonal milieu. TeBG levels are increased by estrogens, thyroid administration and cirrhosis of the liver and may be decreased by androgens, growth hormone and obesity. The biological actions of androgens are exerted on target organs that contain specific androgen receptor proteins. Testosterone leaves the circulation and enters the target cells where it is converted to the more potent androgen dihydrotestosterone by an enzyme 5-alpha-reductase. The major functions of androgens in target tissues include 1) regulation of gonadotropin secretion by the hypothalamic-pituitary axis; 2) initiation and maintenance of spermatogenesis; 3) differentiation of the internal and external male genital system during fetal development; and 4) promotion of sexual maturation at puberty.

Seminiferous Tubules

The seminiferous tubules contain all the germ cells at various stages of maturation and their supporting Sertoli cells. These account for 85-90% of the testicular volume. Sertoli cells are a fixed-population of non-dividing support cells. They rest on the basement membrane of the seminiferous tubules. They are linked by tight junctions. These tight junctions coupled with the close approximation of the myoid cells of the peritubular contractile cell layers serve to form the blood-testis barrier. This barrier provides a unique microenvironment that facilitates spermatogenesis and maintains these germ cells in an immunologically privileged location. This isolation is important because spermatozoa are produced during puberty, long after the period of self-recognition by the immune system. If these developing spermatozoa were not immunologically protected, they would be recognized as foreign and attacked by the body's immune system. Sertoli cells appear to be involved with the nourishment of developing germ cells as well as the phagocytosis of damaged cells. Spermatogonia and young spermatocytes are lower down in the basal compartment of the seminiferous tubule, whereas mature spermatocytes and spermatids are sequestered higher up in the adluminal compartment.

The germinal cells or the spermatogenic cells are arranged in an orderly manner from the basement membrane up to the lumen. Spermatogonia lie directly on the basement membrane, and next in order, progressing up to the lumen, are found the primary spermatocytes, secondary spermatocytes and spermatids. There are felt to be 13 different germ cells representing different stages in the developmental process.

Spermatogenesis is a complex process whereby primitive stem cells or spermatogonia, either divide to reproduce themselves for stem cell renewal or they divide to produce daughter cells that will later become spermatocytes. The spermatocytes eventually divide and give rise to mature cell lines that eventually give rise to spermatids. The spermatids then undergo a transformation into a spermatozoa. This transformation includes nuclear condensation, acrosome formation, loss of most of the cytoplasm, development of a tail and arrangement of the mitochondria into the middle piece of the sperm which basically becomes the engine room to power the tail. Groups of germ cells tend to develop and pass through spermatogenesis together. This sequence of developing germ cells is called a generation. These generations of germ cells are basically in the same stage of development. There are six stages of seminiferous epithelium development. The progression from stage one through stage six constitutes one cycle. In humans the duration of each cycle is approximately 16 days and 4.6 cycles are required for a mature sperm to develop from early spermatogonia. Therefore, the duration of the entire spermatogenic cycle in humans is 4.6 cycles times 16 days equals 74 days.

Hormonal Control of Spermatogenesis

An intimate structural and functional relationship exists between the two separate compartments of the testis, i.e. the seminiferous tubule and the interstitium between the tubules. LH effects spermatogenesis indirectly in that it stimulates androgenous testosterone production. FSH targets Sertoli cells. Therefore, testosterone and PSH are the hormones that are directed at the seminiferous tubule epithelium. Androgen-binding protein which is a Sertoli cell product carries testosterone intracellularly and may serve as a testosterone reservoir within the seminiferous tubules in addition to transporting testosterone from the testis into the epididymal tubule. The physical proximity of the Leydig cells to the seminiferous tubules and the elaboration by the Sertoli cells of androgen-binding protein, cause a high level of testosterone to be maintained in the microenvironment of the developing spermatozoa. The hormonal requirements for initiation of spermatogenesis appear to be independent of the maintenance of spermatogenesis. For spermatogenesis to be maintained like for instance after a pituitary obliteration, only testosterone is required. However, if spermatogenesis is to be re-initiated after the germinal epithelium has been allowed to regress completely, then both FSH and testosterone are required.

Transport-Maturation-Storage of Sperm

Although the testis is responsible for sperm production, the epididymis is intimately involved with the maturation, storage and transport of spermatozoa. Testicular spermatozoa are non-motile and were felt to be incapable of fertilizing ova. Spermatozoa gain progressive motility and fertilizing ability after passing through the epididymis. The coiled seminiferous tubules terminate within the rete testis, which in turn coalesces to form the ductuli efferentes. These ductuli efferentes conduct testicular fluid and spermatozoa into the head of the epididymis. The epididymis consists of a fragile single convoluted tubule that is 5-6 meters in length. The epididymis is divided into the head, body, and tail. Although epididymal transport time varies with age and sexual activity, the estimated transit time of spermatozoa through the epididymis in healthy males is approximately four days. It is during the period of maturation in the head and body of the epididymis that the sperm develop the increased capacity for progressive motility and also acquire the ability to penetrate oocytes during fertilization. The epididymis also serves as a reservoir or storage area for sperm. It is estimated that the extragonadal sperm reservoir is 440 million spermatozoa and that more than 50% of these are located in the tail of the epididymis. The sperm that are stored in the tail of the epididymis enter the vas deferens which is a muscular duct 30-35 cm in length. The contents of the vas are propelled by peristaltic motion into the ejaculatory duct. Sperm are then transported to the outside of the male reproductive tract by emission and ejaculation.

During emission, secretions from the seminal vesicles and prostate are deposited into the posterior urethra. Prior to ejaculation peristalsis of the vas deferens and bladder neck occur under sympathetic nervous control. During ejaculation, the bladder neck tightens and the external sphincter relaxes with the semen being propelled through the urethra via rhythmic contractions of the perineal and bulbourethral muscles. It is true that the first portion of the ejaculate contains a small volume of fluid from the vas deferens which is rich in sperm. The major volume of the seminal fluid comes from the seminal vesicles and secondarily the prostate. The seminal vesicles provide the nourishing substrate fructose as well as prostaglandins and coagulating substrates. A recognized function of the seminal plasma is its buffering effect on the acidic vaginal environment. The coagulum formed by the ejaculated semen liquefies within 20 to 30 minutes as a result of prostatic proteolytic enzymes. The prostate also adds zinc, phospholipids, spermine, and phosphatase to the seminal fluid. The first portion of the ejaculate characteristically contains most of the spermatozoa and most of the prostatic secretions, while the second portion is composed primarily of seminal vesicle secretions and fewer spermatozoa.

FERTILIZATION

Fertilization normally takes place within the uterine tubes after ovulation has occurred. During the menstrual mid cycle, the cervical mucus changes to become more abundant, thinner and more watery. These changes serve to facilitate entry of the sperm into the uterus and to protect the sperm from the highly acidic vaginal secretions. Physiologic changes in the spermatozoa known as capacitation occur within the female reproductive tract in order for fertilization to occur. As the sperm cell interacts with the egg, there is initiation of new flagellar movement called hyperactive motility and morphologic changes in the sperm that result in the release of lytic enzymes and exposure of parts of the sperm's structure known as the acrosome reaction. As a result of these changes, the fertilizing sperm cell is able to reach the oocyte, traverse it's various layers, and become incorporated into the ooplasm of the egg.

CLINICAL FINDINGS

History

The cornerstone of the evaluation of infertile man is a careful history and physical examination. Specific childhood illnesses should be sought including cryptographies, post pubertal mumps orchitis and testicular trauma or torsion. Precocious puberty may indicate the presence of an adrenal-genital syndrome, whereas delayed puberty may indicate Klinefelter's syndrome or idiopathic hypogonadism. Prenatal exposure to diethylstilbesterol should be ascertained because this may cause an increased incidence of epididymal cysts or a slightly increased frequency of cryptorchidism. A detailed history of exposure to occupational and environmental toxins, excessive heat, or radiation should be elicited. Cancer chemotherapy has a dose-dependent and potentially devastating effect on the testicular germinal epithelium. The drug history should be reviewed for anabolic steroids, cimetidine, and spironolactone which can effect the reproductive cycle. Medications like sulfasalazine and nitrofurantoin may effect sperm motility. Illicit drugs and excessive alcohol consumption are associated with a decrease in sperm count and hormonal abnormalities. Previous medical and surgical diseases and their treatment may occasional compromise reproductive function. Men with unilateral undescended testes will have overall semen quality of considerably less than normal. Previous surgical procedures such as bladder neck operations or retroperitoneal lymph node dissection for testicular cancer may cause retrograde ejaculation or absent emission. Diabetic neuropathy may result in either retrograde ejaculation or impotence.

Both the vas deferens and the testicular blood supply can easily be injured during hernia repair. In patients with cystic fibrosis, the vas deferens or epididymis and seminal vesicles are usually absent. Any generalized fever or illness can impair spermatogenesis. The ejaculate may be affected for three months after the event, as spermatogenesis takes about 74 days from initiation to the appearance of mature sperm. There is also a variable transport time in the ducts. Sometimes events that have occurred in the previous 3-6 months are extremely important. Sexual habits including frequency of intercourse, frequency of ejaculation, use of coital lubricants and the patient's understanding of the ovulatory cycle should be discussed. Previous infertility evaluation and treatment and the reproductive history from previous marriages should be ascertained. A history of recurrent respiratory infections and infertility may be associated with the immotile cilia syndrome, in which the sperm count is normal but the spermatozoa are completely non-motile due to ultrastructural defects. Kartagener's syndrome, which is a variant of immotile cilia syndrome, consists of chronic bronchiectasis, sinusitis, situs inversus and immotile spermatozoa. In Young's syndrome, also associated with pulmonary disease, the cilia ultrastructure is normal but the epididymis is obstructed due to inspissated material, and these patients present with azoospermia. Loss of libido associated with headaches, visual abnormalities and galactorrhea may suggest a pituitary tumor. Other medical problems that have been associated with infertility include thyroid disease, seizure disorders, and Liver disease. Interestingly it is not the seizure disorder itself that causes infertility but it is the typical treatment of it with Dilantin (phenytoin). Dilantin decreases FSH. Chronic systemic diseases such as renal disease and sickle cell disease are associated with abnormal reproductive hormonal parameters.

Physical Examination

During the physical examination, particular attention should be paid to discerning features of hypogonadism. Typically this would be viewed as poorly developed secondary sexual characteristics, eunuchoidal skeletal proportions i.e. arm span two inches greater than height, ratio of upper body segment (crown to pubis) to lower body segment (pubis to floor) less than 1, and the lack of normal male hair distribution ie. sparse axillary, pubic, facial, and body hair in conjunction with lack of temporal hair recession. One should be on the lookout also for infantile genitalia ie. small penis, testes, and prostate with under-developed scrotum. One may see a diminished muscular development and mass.

A careful examination of the testes is an essential part of the examination. Normal adult testes are on the average about 4.5 cm long and 2.5 cm wide with a mean volume of about 20 cc. A caliper or orchidometer may be used to measure testicular size. If the seminiferous tubules were damaged before puberty, the testes are small and firm. With postpubertal damage, they are usually small and soft.

Gynecomastia is a consistent feature of a feminizing state. Men with congenital hypogonadism may have associated midline defects such as anosmia, color blindness, cerebellar ataxia, hair lip, and cleft palate. Hepatomegaly may be associated with problems of hormonal metabolism. Proper neck examination may help rule out thyromegaly, a bruit or nodularity associated with disease. Neurologic exam should test the visual fields and reflexes.

Irregularities in the epididymis suggest a previous infection and possible obstruction. Examination may reveal a small prostate with androgen deficiency or slight tenderness (bogginess) in men with prostatic infection. Any penile abnormalities like hypospadias, abnormal curvature, phimosis, should be looked for. The scrotal contents should be carefully palpated with the patient in both the supine and standing positions. Many varicoceles are not visible and may only be discernible when the patient stands or performs the Valsalva maneuver. Varicoceles can often result in a smaller left testis, and a discrepancy in size between the two testes should arouse suspicion. Both vas deferens should be palpated, as 2% of infertile men have congenital absence of the vasa and seminal vesicles.

PRE-TESTICULAR CAUSES OF INFERTILITY

	Hypothalamic disease
	Isolated gonadotropin deficiency (Kallmann's syndrome)
	Isolated LH deficiency ("Fertile eunuch")
	Isolated FSH deficiency
	Congenital hypogonadrotropic syndromes

	Pituitary disease
	Pituitary insufficiency (tumors, infiltrative processes, operation, radiation)
	Hyperprolactinemia
	Hemochromatosis
	Exogenous hormones (estrogen-androgen excess, glucocorticoid excess, hyper and hypothyroidism).

HYPOTHALAMIC DISEASE

Kallmann's syndrome which is an isolated gonadotropin (LH and FSH) deficiency occurs in both a sporadic and familial form and although uncommon i.e. 1 in 10,000 men, it is second to Klinefelter's syndrome as a cause of hypogonadism. The syndrome is often associated with anosmia, congenital deafness, hair lip, cleft palate, craniofacial asymmetry, renal abnormalities, color blindness. The hypothalamic hormone GnRH appears to be absent. If exogenous GnRH is administered, both LH and FSH are released from the pituitary. Except for the gonadotropin deficiency, anterior pituitary function is intact. The syndrome appears to be inherited either as an autosomal recessive trait or an autosomal dominant trait with incomplete penetrance. The differential diagnosis should include delayed puberty. Kallmann's syndrome distinguishing features though are testes less than 2 cm in diameter and positive family history with the presence of anosmia. "Fertile eunuch" are individuals with isolated LH deficiency. They have eunuchoid proportions with variable degrees of virilization and gynecomastia. They characteristically have large testes and semen containing a few sperm. Plasma FSH levels are normal but both the serum LH and testosterone concentrations are low normal. The cause appears to be a partial gonadotropin deficiency in which there is adequate LH to stimulate testosterone production with resultant spermatogenesis but insufficient testosterone to promote virilization. In isolated FSH deficiency which is rare, patient's are normally virilized and have normal testicular size and baseline levels of LH and testosterone. Sperm counts range from O to a few sperm. Serum FSH levels are low and do not respond to GnRH stimulation. Congenital hypogonadotropic syndromes are associated with secondary hypogonadism and a multitude of other somatic findings. Prader-Willi syndrome is characterized by hypogonadism, hypomentia, hypotonia at birth and obesity. Laurence-Moon-Bardet-Biedel syndrome is an autosomal recessive trait characterized by mental retardation, retinitis pigmentosa, polydactyly and hypogonadism. These syndromes are felt to be due to a defect in hypothalamic deficiency of GnRH.

PITUITARY DISEASE

Pituitary insufficiency may result from tumors, infarctions, iatrogenic causes like surgery and radiation or one of several infiltrative processes. If pituitary insufficiency occurs prior to puberty, growth retardation associated with adrenal and thyroid deficiency is the major clinical presentation. Hypogonadism that occurs in a sexually mature male usually has its origin in a pituitary tumor. Decreasing libido, impotence and infertility may occur years before symptoms of an expanding tumor i.e. such as headaches, visual abnormalities, or thyroid/adrenal hormone deficiency. Once an individual has passed through normal puberty, it takes a long time for secondary sexual characteristics to disappear unless adrenal insufficiency is present. The testes will eventually become small and soft. The diagnosis is made by low serum testosterone levels with low or low normal plasma gonadotropins concentrations. Depending on the degree of panhypopituitarism, plasma corticosteroids will be reduced with plasma TSH and growth hormone levels.

Hyperprolactinemia can cause both reproductive and sexual dysfunction. Prolactin-secreting tumors of the pituitary gland whether from a microadenoma (less than 10 mm) or a macroadenoma, can result in loss of libido, impotence, galactorrhea, gynecomastia and alter spermatogenesis. Patients with a macroadenoma usually first present with visual field abnormalities and headaches. They should undergo CT or MRI scanning of the pituitary and laboratory testing of anterior pituitary, thyroid and renal function. These patients have low serum testosterone levels but basal serum levels of LH and FSH are either low or low normal and reflect an inadequate pituitary response to depressed testosterone.

Approximately 80% of men with hemochromatosis have testicular dysfunction. Their hypogonadism may be secondary to iron deposition in the liver or may be primarily testicular as a result of iron deposition in the testes. Iron deposits have also been found in the pituitary, implicating this gland as the major site of abnormality.

With regard to the role of exogenous hormones, adrenocortical tumors, Sertoli cell tumors, interstitial cell tumors of the testes may all at times be estrogen-producing. Hepatic cirrhosis is associated with increased endogenous estrogens. Estrogens act primarily by suppressing pituitary gonadotropin secretion, resulting in secondary testicular failure. Androgens can also suppress pituitary gonadotropin secretion thereby leading to secondary testicular failure. The current use of anabolic steroids by certain athletes may result in temporary sterility. Endogenous androgen excess may be due to an androgen-producing adrenocortical tumor or testicular tumor but more likely to congenital adrenal hyperplasia. As a consequence of this disease, the production of androgenic steroids by the adrenal cortex is increased, resulting in premature development of secondary sexual characteristics and abnormal phallic enlargement. The testes failed to mature because of gonadotropin inhibition and are characteristically small. In the absence of precocious puberty, the diagnosis is extremely difficult since excessive virilization is difficult to detect in an otherwise normally sexually mature man. Careful laboratory evaluation is essential. Infertility caused by documented congenital adrenal hyperplasia is treatable with corticosteroids. Physicians have used corticosteroids in individuals with idiopathic infertility, but unless these abnormalities can be documented, steroid therapy has no place.

Sometimes glucocorticoid excess (prednisone usage) is exogenous in the therapy of ulcerative colitis, asthma, or rheumatoid arthritis. The result is decreased spermatogenesis. The elevated plasma cortisone levels depress LH secretion and can cause secondary testicular dysfunction. Correction of the glucocorticoid excess results in improvement in spermatogenesis. Hyper and hypothyroidism can alter spermatogenesis. Hyperthyroidism effects both pituitary and testicular function with alterations in the secretion of releasing hormones and increased conversion of androgens to estrogens.

TESTICULAR CAUSES OF INFERTILITY

- Chromosomal abnormalities (Klinefelter's syndrome, XX disorder (sex reversal syndrome), XYY syndrome)

- Noonan's syndrome (male Turner's syndrome)

- Myotonic dystrophy

- Bilateral anorchia (vanishing testes syndrome)

- Sertoli-cell-only syndrome (germinal cell aplasia)

- Gonadotoxins (drugs, radiation)

- Orchitis

- Trauma

- Systemic disease (renal failure, hepatic disease, sickle cell disease)

- Defective androgen synthesis or action

- Cryptorchidism

- Varicocele

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Stevens-Johnson Syndrome

Introduction

Background

First described in 1922, Stevens-Johnson syndrome (SJS) is an immune-complex–mediated hypersensitivity complex that is a severe expression of erythema multiforme. It is known by some as erythema multiforme major, but disagreement exists in the literature. Most authors and experts consider SJS and toxic epidermal necrolysis (TEN) different manifestations of the same disease. For that reason, many refer to the entity as SJS/TEN. SJS typically involves the skin and the mucous membranes. While minor presentations may occur, significant involvement of oral, nasal, eye, vaginal, urethral, GI, and lower respiratory tract mucous membranes may develop in the course of the illness. GI and respiratory involvement may progress to necrosis. SJS is a serious systemic disorder with the potential for severe morbidity and even death. Missed diagnosis is common.

Combined effects of overweight and smoking in late adolescence on subsequent mortality: nationwide cohort study

Martin Neovius, postdoctoral fellow^1,2, Johan Sundström, associate professor³, Finn Rasmussen, professor²

¹ Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute, Karolinska University Hospital, SE-171 76 Stockholm, Sweden, ² Department of Public Health Sciences, Karolinska Institute, Karolinska University Hospital (Norrbacka), ³ Department of Medical Sciences, Uppsala University Hospital, SE-75185 Uppsala, Sweden

Abstract

Abstract
Introduction
Methods
Results
Discussion
References

Objective To investigate the combined effects on adult mortality of overweight and smoking in late adolescence.

Design Record linkage study with Cox proportional hazard ratios adjusted for muscle strength, socioeconomic position, and age.

Setting Swedish military service conscription register, cause of death register, and census data.

Participants 45 920 Swedish men (mean age 18.7, SD 0.5) followed for 38 years.

Main outcome measures Body mass index (underweight (BMI <18.5), normal weight (18.5-24.9), overweight (25-29.9), and obesity (30)), muscle strength, and self reported smoking (non-smoker, light smoker (1-10 cigarettes/day), heavy smoker (>10/day)) at mandatory military conscription tests in 1969-70. All cause mortality.

Results

Over 1.7 million person years, 2897 men died. Compared with normal weight men (incidence rate 17/10 000 person years, 95% confidence interval 16 to 18), risk of mortality was increased in overweight (hazard ratio 1.33, 1.15 to 1.53; incidence rate 23, 20 to 26) and obese men (hazard ratio 2.14, 1.61 to 2.85; incidence rate 38, 27 to 48), with similar relative estimates in separate analyses of smokers and non-smokers. No increased risk was detected in underweight men (hazard ratio 0.97, 0.86 to 1.08; incidence rate 18, 16 to 19), though extreme underweight (BMI <17)> ratio 1.33, 1.07 to 1.64; incidence rate 24, 19 to 29). The relative excess risk due to interaction between BMI and smoking status was not significant in any stratum. Furthermore, all estimates of interaction were of small magnitude, except for the combination of obesity and heavy smoking (relative excess risk 1.5, –0.7 to 3.7). Compared with non-smokers (incidence rate 14, 13 to 15), risk was increased in both light (hazard ratio 1.54, 1.41 to 1.70; incidence rate 15, 14 to 16) and heavy smokers (hazard ratio 2.11, 1.92 to 2.31; incidence rate 26, 24 to 27).

Conclusions Regardless of smoking status, overweight and obesity in late adolescence increases the risk of adult mortality. Obesity and overweight were as hazardous as heavy and light smoking, respectively, but there was no interaction between BMI and smoking status. The global obesity epidemic and smoking among adolescents remain important targets for intensified public health initiatives.

Introduction

Abstract
Introduction
Methods
Results
Discussion
References

The obesity pandemic seems to affect children and adolescents more than adults, with higher relative increases in overweight and obesity than in adults in several parts of the world.^{1 2} In middle aged adults, obesity (body mass index (BMI) 30) increases the risk of mortality twofold to threefold compared with people of normal weight (BMI 18.5-24.9).^{3 4 5 6} Whether risk of mortality is also increased in overweight adults (BMI 25-29.9) is debatable,^{6 7 8 9 10} with reports of both lower^{6 7} and higher mortality.^{3 5 9 10} The conflicting views mainly concern handling of possible confounding because of smoking and reverse causation (with low BMI potentially being caused by pre-existing illnesses).¹⁰ The common finding of excess mortality in underweight people might be an artefact caused by insufficient adjustment for smoking.^{7 11 12} Access to data on smoking in a sufficiently large sample unaffected by pre-existing illness would circumvent such problems. Available studies of younger people, however, are limited by coarse BMI modelling (obese v non-obese),¹³ having few overweight participants,¹⁴ lacking data on important covariates such as smoking and socioeconomic position,¹⁵ or analysing women only.¹²

Smoking rates in adolescents remain high,¹⁶ with a marked increase over the past decades in some countries.¹⁷ In adults in the United States, smoking was ranked as the behavioural risk factor resulting in the most excess deaths in 2000, closely followed by diet and activity patterns, accounting for 18.1% and 16.6% of excess deaths, respectively.¹⁸ In adolescents as well as in adults, smoking and overweight or obesity are the two most important modifiable risk factors for mortality in the Western world. While smoking is already a major problem in developing countries, obesity is becoming one in all regions of the world except the very poorest.¹⁹ Despite that, the combined effects on mortality associated with these two risk factors and their interaction in late adolescence are not known.

We hypothesised that overweight and smoking in late adolescence increase the risk of mortality and that their effects are synergistic. Our secondary hypothesis was that excess risk in underweight people is accounted for by smoking. We investigated these hypotheses using a large nationwide cohort of men from a military conscription registry.

Methods

Abstract
Introduction
Methods
Results
Discussion
References

Sample
The study was based on nationwide military conscription data from 49 321 Swedish men born 1949-51 who performed mandatory military conscription tests in 1969-70. The background of the military conscription registry data has been presented in detail elsewhere.²⁰ Only 2-3% of all Swedish men were exempt from conscription at this time, in most cases because of severe handicaps or congenital disorders. The men we included accounted for 97.7% of all conscripts in 1969-70, with the 2.3% remaining born before 1949. Based on the unique personal identification number assigned to each Swedish citizen, we performed record linkage of the conscription registry and the cause of death registry. To be included in the current study, men were required to have performed their induction tests between the ages of 16 and 20 and have recorded data on measured weight and height and self reported smoking habits at conscription. The age restriction was used to keep the sample homogenous by age. Although most men in Sweden perform their conscription test the year they turn 18, some test at other ages.

Baseline examinations
We used WHO defined categories of body mass index (BMI, weight (kg)/(height (m)²): underweight (<18.5),> overweight (25-29.9), and obese (30).²¹

The conscription registry contains a small number of extreme values on weight, height, and BMI, which might be true values or represent errors in measurement or data entry. To minimise errors of random misclassifications, we applied exclusion limits for height (150 or 210 cm), weight (40 or 150 kg), and BMI (15 or 60). We categorised smoking status into three levels (non-smoker, 1-10 (light smoker), >10 cigarettes/day (heavy smoker)) using a questionnaire. Covariates considered were muscle strength (leg extension, arm flexion, and hand grip), household socioeconomic status, and age at testing. We retrieved parental socioeconomic status (white collar, blue collar, self employed, other) in 1970 from the population and housing census in 1970. We used the highest of the maternal and paternal socioeconomic status as household socioeconomic status. If both were missing, we used the registered socioeconomic status of the military conscript.

Follow-up and outcomes
Mortality data were retrieved from the national cause of death registry until 1 September 2007. Participants who did not die during follow-up were censored at that time or at time of emigration.

Statistical analysis
Data were analysed with SAS (version 9, SAS Institute, Cary, NC) and Stata (version 10.0, College Station, TX). Unadjusted incidence rates (deaths/10 000 person years) and Kaplan-Meier failure functions were used to present the absolute risk of death. A Cox proportional hazards model was used to model time to event for estimation of relative risks of death, unadjusted and adjusted for potential confounding variables.²² Reference categories were normal BMI and non-smoker.

Initially we fitted unadjusted models for BMI, smoking, and both variables combined. These three models were thereafter adjusted for muscle strength, socioeconomic status, and age at testing. Multivariable adjusted BMI models were then repeated in four categories of smoking (non-smokers, smokers, light smokers, and heavy smokers) and smoking models were repeated in four categories of BMI (underweight, normal weight, overweight, and obesity).

In our secondary analyses, we fitted an additional model with the underweight category split into moderate (BMI 17-18.4) and extreme underweight (BMI<17)> Also, for comparison with previous work on adolescent women,¹² we fitted a model with BMI 18.5-21.9 as reference to investigate whether small increases in BMI (22.0-24.9) were associated with excess risk.

We investigated biological interaction, as defined by Rothman,²³ between BMI and smoking status by calculating the relative excess risk because of the interaction (RERI) by using the methods outlined by Andersson et al.²⁴ In this analysis we calculated the separate contributions to the relative risk of death from the BMI category, smoking category, and the interaction between the two. In the absence of a biological interaction between BMI and smoking status, the relative excess risk will be 0.

Using bootstrap estimated 95% confidence intervals obtained by re-sampling 45 000 individuals 1000 times, we compared the hazard ratios for heavy smoking (v non-smoking) and obesity (v normal weight) and those for light smoking (v non-smoking) and overweight (v normal weight) in the fully adjusted model.

Few data were missing, and Cox regressions were based on complete case analyses.

Results

Abstract
Introduction
Methods
Results
Discussion
References

Of 50 398 participants in the database, 889 had no recorded data on smoking, while 951 had weight, height, or BMI outside the acceptable limits. Of the 48 691 remaining participants, we excluded 2771 as they were aged >20 at the conscription test, leaving a final 45 920 participants for analysis. Table 1 shows details of the participants. Tables 2 and 3 show deaths according to BMI category and smoking.


Table 1 Baseline characteristics of study population* according to BMI. Figures are numbers (percentage) or means (SD) for continuous variables

Underweight Normal weight Overweight Obesity Total No (%) in group 6325 (13.8) 36 605 (79.7) 2623 (5.7) 367 (0.8) 45 920 (100) Anthropometry: Height (cm) 178.6 (6.5) 178.1 (6.3) 177.7 (6.4) 177.2 (6.7) 178.1 (6.3) Weight (kg) 56.3 (4.6) 66.7 (6.8) 84.1 (7.4) 101.1 (10.0) 66.6 (9.2) BMI 17.6 (0.7) 21.0 (1.6) 26.6 (1.3) 32.2 (2.0) 21.0 (2.6) Smoking: Non-smoker 2325 (37) 15 430 (42) 1107 (42) 145 (40) 19 007 (41) 1-10/day 2286 (36) 11 771 (32) 711 (27) 84 (23) 14 852 (32) >10/day 1714 (27) 9404 (26) 805 (31) 138 (38) 12 061 (26) Covariates: Age (years) 18.7 (0.5) 18.7 (0.5) 18.7 (0.5) 18.7 (0.5) 18.7 (0.5) Hand grip 549 (85) 613 (96) 648 (107) 653 (112) 607 (98) Arm flexion 311 (57) 375 (76) 424 (88) 438 (89) 369 (79) Leg extension 459 (83) 542 (99) 601 (110) 623 (122) 535 (103) Socioeconomic status: White collar 2953 (47) 15 549 (42) 913 (35) 99 (27) 19 514 (43) Blue collar 2308 (37) 13 723 (38) 1198 (46) 198 (54) 17 427 (38) Self employed 842 (13) 6229 (17) 448 (17) 63 (17) 7582 (17) Other 220 (3) 1088 (3) 64 (2) 7 (2) 1379 (3) Incidence of death: Deaths 400 2231 217 49 2897 Person years 228 529 1 321 988 94 915 13 052 1 658 485 Deaths/10 000 person years (95% CI) 17.5 (15.8 to 19.2) 16.9 (16.2 to 17.6) 22.9 (19.8 to 25.9) 37.5 (27.0 to 48.1) 17.5 (16.8 to 18.1)

* Data missing on leg strength for 8, arm strength for 17, and socioeconomic status for 18.

Body mass index (kg/m²): underweight <18.5, src="http://www.bmj.com/math/ge.gif" alt="≥" border="0">30.

Measured in newtons.

Table 2 Deaths in smokers and non-smokers according to BMI* category

Non-smoker (n=18 990) Smoker (n=26 894) Light smoker (1-10/day) (n=14 846) Heavy smoker (>10/day) (n=12 048) Total (n=45 884) Person years 689 628 968 138 536 243 431 895 1 657 766 Deaths (total) 806 2072 976 1096 2878 BMI category: Underweight 96 301 138 163 397 Normal 634 1582 760 822 2216 Overweight 63 153 68 85 216 Obese 13 36 10 26 49

*Body mass index (kg/m²): underweight <18.5, src="http://www.bmj.com/math/ge.gif" alt="≥" border="0">30.

Deaths and person years are for participants with data on all covariates used in Cox regressions in tables 4 and 5. Therefore numbers do not equal those shown in table 1.

Table 3 Deaths in BMI* categories according to smoking status

Underweight (n=6320) Normal weight (n=36 575) Overweight (n=2622) Obese (n=367) Total (n=45 884) Person years 228 431 1 321 398 94 885 13 052 1 657 766 Deaths (total) 397 2216 216 49 2878 Smoking category: Non-smoker 96 634 63 13 806 Light smoker (1-10/day) 138 760 68 10 976 Heavy smoker (>10/day) 163 822 85 26 1096

*Body mass index (kg/m²): underweight <18.5, src="http://www.bmj.com/math/ge.gif" alt="≥" border="0">30.

Deaths and person years are for participants with data on all covariates used in Cox regressions in tables 4 and 5. Therefore numbers do not equal those shown in table 1.

Unadjusted survival analyses
During 1.7 million person years (median 38 years) of follow-up, 2897 men died and 1806 emigrated. Figure 1 shows the cumulative mortality during follow-up according to obesity and smoking status.

Fig 1 Cumulative mortality according to obesity status (underweight (BMI <18.5), src="http://www.bmj.com/math/ge.gif" alt="≥" border="0">30)) and smoking status over 38 years of observation

The incidence of death was the lowest in normal weight men and highest in obese men (table 1, fig 1). In unadjusted models with normal weight participants as reference, the risk of mortality was significantly higher for overweight (hazard ratio 1.35, 95% confidence interval 1.17 to 1.55, P<0.001)> (2.25, 1.70 to 2.98, P<0.001)> (1.04, 0.93 to 1.15, P=0.51). With non-smokers as the reference category, there was a gradually increasing risk from men who smoked 1-10 cigarettes/day (1.55, 1.41 to 1.70, P<0.001) to >10 cigarettes/day (2.18, 1.99 to 2.39, P<0.001)> unadjusted analyses. The absolute risks of death were 14.2 (13.3 to 15.1), 15.2 (14.2 to 16.2), and 25.5 (24.0 to 27.0) per 10 000 person years in non-smokers, light smokers, and heavy smokers, respectively.

Multivariable adjusted survival analyses
The significantly increased risks in overweight and obese men remained in our multivariable adjusted analyses of obesity status as a predictor for mortality, with adjustment for smoking, muscle strength, socioeconomic status, and age (table 4). The hazard ratios changed little when we included or excluded smoking as a covariate or analysed smokers and non-smokers separately. When we further stratified participants into light and heavy smokers, the direction of the point estimates for the BMI categories remained the same, although the confidence intervals widened. The hazard ratio among underweight men did not differ significantly from that in normal weight men in any category.

Table 4 Relative risks of premature death estimated by Cox regression analysis* (with 95% confidence intervals) according to categories of BMI and smoking

BMI Total (n=45 884) Smoking status Base model Adjusted also for smoking Non-smokers (n=18 990) Smokers (n=26 894) Light (1-10/day) (n=14 846) Heavy (>10/day) (n=12 048) Underweight 1.00 (0.89 to 1.12), P=0.99 0.97 (0.86 to 1.08), P=0.56 0.94 (0.75 to 1.18), P=0.62 0.97 (0.85 to 1.11), P=0.69 0.91 (0.75 to 1.10), P=0.32 1.05 (0.88 to 1.25), P=0.61 Normal weight 1 1 1 1 1 1 Overweight 1.34 (1.16 to 1.55), P<0.001 1.33 (1.15 to 1.53), P<0.001 1.37 (1.05 to 1.79), P=0.02 1.35 (1.14 to 1.60), P<0.001 1.44, (1.11 to 1.86), P=0.006 1.23 (0.98 to 1.54), P=0.08 Obesity 2.22 (1.66 to 2.95), P<0.001 2.14 (1.61 to 2.85), P<0.001 2.16 (1.24 to 3.76), P=0.007 2.23 (1.60 to 3.12), P<0.001 1.83 (0.98 to 3.42), P=0.06 2.27 (1.53 to 3.38), P<0.001

*All models adjusted for muscular strength, socioeconomic status, and age.

Body mass index (kg/m²): underweight <18.5, src="http://www.bmj.com/math/ge.gif" alt="≥" border="0">30.

Similarly, the hazard ratios for smoking remained unchanged before and after adjustment for BMI status (table 5). Although the point estimates differed in magnitude across BMI categories, all were in the same direction and all but one were significant.

Table 5 Relative risks of premature death estimated by Cox regression analysis* (with 95% confidence intervals) according to categories of smoking and BMI

Smoking Total (n=45 884) Obesity status Base model Adjusted also for BMI Underweight (n=6320) Normal weight (n=36 575) Overweight (n=2622) Obese (n=367) Non-smokers 1 1 1 1 1 1 Light (1-10/day) 1.53 (1.40 to 1.68), P<0.001 1.54 (1.41 to 1.70), P<0.001 1.47 (1.13 to 1.91), P=0.004 1.56 (1.40 to 1.73), P<0.001 1.66 (1.17 to 2.35), P=0.005 1.36 (0.60 to 3.11), P=0.46 Heavy (>10/day) 2.11 (1.93 to 2.32), P<0.001 2.11 (1.92 to 2.31), P<0.001 2.36 (1.83 to 3.04), P<0.001 2.09 (1.89 to 2.32), P<0.001 1.85 (1.33 to 2.57), P<0.001 2.17 (1.11 to 4.23), P=0.02

*All models adjusted for muscular strength, socioeconomic status, and age.

Body mass index (kg/m²): underweight <18.5, src="http://www.bmj.com/math/ge.gif" alt="≥" border="0">30.

Subcategories of BMI and risk of mortality
Although being underweight (BMI <18.5)> with increased risk compared with normal weight, further stratification showed that extremely underweight men (BMI <17)> increased risk of about the same magnitude (adjusted hazard ratio 1.33, 1.07 to 1.64, P=0.009; unadjusted 1.47, 1.20 to 1.80, P<0.001)> normal weight reference category.

Further stratification of the normal weight group also showed significant graded increases from a BMI of 18.5-21.9 (reference) to BMI 22-24.9 (1.15, 1.05 to 1.27, P=0.004).

Combined effects of smoking and BMI
Figure 2 shows the combined effects of smoking and obesity status. The unadjusted mortality rate was similar for obese non-smokers and normal weight heavy smokers. After adjustment, the difference in hazard ratios between heavy smoking (v non-smoking) and obesity (v normal weight) was –0.02 (bootstrap obtained 95% confidence interval –0.69 to 0.64, P=0.96). Similarly, overweight and light smoking were associated with similar increases in risk of mortality with a difference in hazard ratios between light smoking (v non-smoking) and overweight (v normal weight) of 0.22 (–0.04 to 0.45, P=0.08).

Fig 2 Unadjusted incidence rates for mortality showing combined effects of BMI and smoking (n=45 920). Light smoker=1-10 cigarettes/day; heavy smoker >10 cigarettes/day

Compared with normal weight men who did not smoke, the hazard ratios for groups defined by BMI and smoking status were large (1.31 to 4.74; table 6) and highly significant (P<0.001> P=0.02) for all but two groups: moderately underweight non-smokers (0.92, 0.72 to 1.17, P=0.48) and extremely underweight non-smokers (1.24, 0.81 to 1.91). Overweight and obese heavy smokers, respectively, had hazard ratios >2 (2.55, 2.03 to 3.20, P<0.001)> close to five times higher (4.74, 3.20 to 7.03, P<0.001) than normal weight non-smokers.


Table 6 Adjusted* hazard ratios for mortality according to BMI and smoking

BMI and smoking Hazard ratio (95% CI) P value Extreme underweight (BMI<17) Non-smoker 1.24 (0.81 to 1.91) 0.32 Light smoker 1.80 (1.25 to 2.59) 0.002 Heavy smoker 3.09 (2.26 to 4.23) <0.001 Moderate underweight (BMI 17-18.4) Non-smoker 0.92 (0.72 to 1.17) 0.48 Light smoker 1.31 (1.06 to 1.61) 0.01 Heavy smoker 2.00 (1.64 to 2.44) <0.001 Normal weight (BMI 18.5-24.9) Non-smoker 1.00 Light smoker 1.56 (1.40 to 1.73) <0.001 Heavy smoker 2.10 (1.89 to 2.33) <0.001 Overweight (BMI 25-29.9) Non-smoker 1.36 (1.05 to 1.77) 0.02 Light smoker 2.33 (1.81 to 3.00) <0.001 Heavy smoker 2.55 (2.03 to 3.20) <0.001 Obesity (BMI 30) Non-smoker 2.14 (1.24 to 3.72) 0.01 Light smoker 2.88 (1.54 to 5.39) 0.00 Heavy smoker 4.74 (3.20 to 7.03) <0.001

*Adjusted for muscle strength, socioeconomic status, and age.

Light smoking 1-10 cigarettes/day, heavy smoking >10 cigarettes/day.

Figure 3 shows the separate contributions to the relative risk of death from BMI and smoking status, as well as the interaction between the two. The relative excess risk due to interaction between smoking and BMI status did not reach significance in any category of BMI. Furthermore, the point estimates were generally small: the interaction between mild smoking and either underweight, overweight, or obesity resulted in contributions to the relative risk of –0.1 to 0.4, and heavy smoking with underweight or overweight increased the relative risk with 0.1 over and above what would be expected from the two risk factors without any interaction effect. Though not significant, however, the combined effect of obesity and heavy smoking was large, with a relative excess risk due to interaction of 1.5.

Fig 3 Relative risks of death with separate contributions from the exposure categories BMI status, smoking status, and their interaction, with point estimates and 95% confidence intervals for relative excess risk due to interaction (RERI) between BMI and smoking status. Models adjusted for muscle strength, socioeconomic status, and age

Discussion

Abstract
Introduction
Methods
Results
Discussion
References

In this follow-up study of men aged 16-19 at baseline we found a J shaped relation between BMI and premature death in non-smokers as well as in light and heavy smokers. Compared with men of normal weight, we found excess risks for overweight and obese men, irrespective of smoking status. Although the combination of heavy smoking and obesity was associated with a large increase in risk, we found no significant interaction between BMI and smoking status. The risks of mortality for underweight, overweight, and obesity were of similar magnitude in models that analysed smokers and non-smokers separately, as well as in models with multivariate adjustment. The excess risk conferred by obesity in late adolescence was of similar magnitude as smoking >10 cigarettes/day, and the risk associated with overweight was similar to that of 1-10/day.

Absence of interaction between BMI and smoking
Most previous studies on the relation between BMI in late adolescence and mortality have not had access to data on smoking.^{13 15 25} In one study of US female nurses based on recalled BMI at age 18, van Dam et al found a similar relative risk of mortality across categories of BMI in non-smokers as in the sample as a whole, describing a linear rather than a J shaped association.¹² This might support the notion of an absence of interaction. Our findings in Swedish men largely agree with that study. We also explicitly investigated potential synergistic effects between smoking and categories of BMI and found no significant interaction between light or heavy smoking with either underweight or overweight. The combination of obesity and heavy smoking was associated with a seemingly large relative excess risk because of interaction, though it did not reach significance.

Overweight and mortality
The finding of a significantly increased risk of death with obesity agrees with several previous studies in late adolescence.^{12 13 15} Regarding overweight, the evidence is more mixed for older adults,^{3 4 5 6 7} while few previous studies have investigated this issue in late adolescence for men. For US women, data based on recalled BMI at age 18 have previously shown increased relative risks for all cause mortality in overweight women compared with women with BMI 18.5-21.9.¹² Significantly increased risks of death for Norwegian men and women aged 14-19 with a BMI between the 85th and 94th centile have also been reported, but no data were available on any potential confounders.¹⁵ Our findings constitute an extension of these previous findings. The current study and the two previous^{12 15} studies indicate adolescent overweight to be a serious health concern, in contrast with some reports from adult samples.^{6 7 8} The higher hazard ratios found in adolescent women might partly be caused by the different choice of reference category (18.5-21.9 v 18.5-24.9), which probably inflated the relative risks in the study by van Dam et al.¹² When we re-analysed our data with BMI 18.5-21.9 as reference category, the hazard ratios for overweight increased to 1.41 (1.22 to 1.63), and we also found significantly increased risks in the upper range of the normal weight category (BMI 22.0-24.9; 1.15, 1.05 to 1.27, P=0.004).

Underweight and mortality
Underweight has also been found to be significantly associated with small increases in relative risk of mortality in some^{3 5 7} but not all previous studies.^{11 12} We found no significant increase in risk in underweight men. A potential contributing factor to this might be that our study was less likely to be affected by reverse causality—that is, that a low BMI is caused by (rather than the cause of) ill health—than studies on older adults. Although authors often try to adjust for pre-existing illness by excluding deaths in the early years of follow-up, this eliminates only those participants progressing quite rapidly to death. As we investigated 18 year olds, the baseline risk of pre-existing illness was probably much lower than among people aged 30, 40, and 50. Our finding also agrees with that of van Dam et al in adolescent women, based on recalled BMI.¹² When we further stratified the underweight group, however, we found a significantly increased risk of death, similar to that seen in overweight, for men with a BMI <17.> that, at least in this age group, there might be a relevant threshold somewhere within the underweight category.

Biological mechanisms
Overweight and obesity are both associated with insulin resistance, higher blood pressure, and adverse blood lipid profiles, providing a biological basis for our findings. These are likely to result in a greater incidence of type 2 diabetes and cardiovascular morbidity²⁶ and have also been linked to several types of cancer.²⁷ The biological basis for the increased risk in the extremely underweight is less clear but might relate to greater susceptibility to infections and generally reduced ability to withstand or cope with illnesses.

Neither light nor heavy concurrent smoking synergistically exacerbated the risks associated with underweight or overweight. Whether the combination of heavy smoking and obesity has synergistic effects will require further study as the point estimate in this study was large but did not reach statistical significance.

Public health impact
In Sweden, overweight has tripled and obesity quintupled in adolescent men since the baseline measurements in this study,²⁸ while smoking and underweight have halved.^{29 30} Internationally, marked increases over the past decades have been observed in overweight and obesity¹⁹ and also in smoking in adolescence in some countries.¹⁷ Although there was little evidence of synergistic effects, except for combined heavy smoking and obesity, compared with normal weight non-smokers the risk of mortality was more than doubled for overweight light smokers, tripled for obese light smokers, and close to quintupled for obese heavy smokers. In addition, although moderate underweight at this age did not seem to confer any increased risk of mortality, extreme underweight did even after adjustment for smoking. This indicates that the relation between BMI and mortality is not linear in adolescent men, as has been suggested for adolescent women¹² and adults.^{4 11} Hence it might be important to search for explanations other than smoking for the increased mortality in this subgroup.

Strengths and limitations
Our study was representative of adolescent men and had a long follow-up, measured instead of self reported height and weight, and data on smoking habits, muscle strength, and socioeconomic status. With military conscription being mandatory and participation enforced by law in the period investigated, included participants constitute close to the entire Swedish male population. Self reported BMI is known to be affected by under-reporting, which increases with increasing BMI,^{31 32 33 34} but as trained personnel measured height and weight in this study, the risks of measurement errors were small and further reduced by the exclusion limits we applied.

There were, however, several limitations. Firstly, we had no data on women as military conscription was mandatory only for men in Sweden. US data on recalled BMI at age 18 in women, however, strongly suggest that the associations also hold for women.¹² Secondly, although BMI is a widely used proxy for fatness, it takes neither the muscle v fat mass relation nor the distribution of fatness into account. Some degree of misclassification is therefore inevitable. The access to data on muscle strength at least partly mitigated this problem, although more direct measures of adiposity would have been preferable, and measures of fat distribution helpful.³⁵ Thirdly, we cannot exclude effects of residual confounding caused by unmeasured or imperfectly measured confounders. Finally, the risk of mortality might also be related to changes in weight and smoking during follow-up, for which we had no data. Regarding weight change from 18 years to middle age, van Dam et al did not find any substantial increases in risk from 15 v <4> women (hazard ratio 1.05, 0.84 to 1.31). The impact of potential changes in smoking is less clear, but a greater rate of smoking cessation than initiation might have resulted in underestimation of the risks of smoking.

Summary and conclusion
In summary, we found that overweight and obesity in late adolescence is associated with premature death, regardless of smoking status. Obesity and overweight were as hazardous as heavy and light smoking, respectively, and there was no interaction between smoking and obesity status. The findings indicate that from a mortality perspective targets for young men should be within the non-smoking, normal weight range, and that overweight, obesity, and smoking among adolescents might be good targets for intensified public health initiatives.

References

Abstract
Introduction
Methods
Results
Discussion
References

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