Medication Summary
Patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism who do not desire fertility should have gonadal steroid replacement therapy, including testosterone in males and estrogen-progestin in females, unless contraindicated. Fertility options include either GnRH (gonadorelin [no longer commercially available in the US]) or gonadotropin-based regimens. Clomiphene may also be used in women with hypothalamic amenorrhea.
Androgens
Class Summary
Androgen replacement in males with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism restores libido, erectile function, and well-being. In addition, androgen replacement promotes the development of secondary sex characteristics (eg, facial, axillary, and pubic hair) and increases muscle strength. A short course of androgens in infancy leads to penile growth in infants with micropenis. Androgen replacement also improves bone density and may prevent osteoporosis. Either parenteral or transdermal testosterone is the drug of choice for androgen replacement. Orally administered alkylated androgens should be avoided because of the risk of serious hepatic toxicity, including peliosis hepatitis, cholestasis, and hepatocellular carcinoma.
Testosterone (Aveed, Depo-Testosterone, Delatestryl, Testopel)
Promotes and maintains secondary sex characteristics in males who are androgen deficient. Several testosterone salts (eg, enanthate, cypionate, undecanoate) are available in a long-acting oil-based preparations.
Testosterone transdermal (Androderm, AndroGel, Testim, Axiron, Fortesta)
Androgenic anabolic steroid indicated for testosterone replacement. Several preparations are available as topical gels or transdermal patches. Patches are changed daily. Testosterone is a schedule III controlled substance.
Testosterone intranasal (Natesto)
Testosterone promotes growth and development of male sex organs and maintains secondary sex characteristics in androgen-deficient males. Indicated for replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone (congenital or acquired) including primary hypogonadism and hypogonadotropic hypogonadism.
Steroid hormones
Class Summary
Estrogen replacement therapy in females with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism promotes the development of secondary sex characteristics, including breast development and menstrual function, and it may prevent osteoporosis. Oral contraceptives may be used as replacement therapy in young women. A thorough discussion of estrogen replacement therapy in older (postmenopausal women) is beyond the scope of this review.
Conjugated estrogens (Premarin)
Induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics.
Ethinyl estradiol (Estinyl)
Induces the synthesis of DNA, RNA, and various proteins in target tissues. Promotes development of secondary sex characteristics.
Estradiol (Estrace)
Increases synthesis of DNA, RNA, and many proteins in target tissues.
Transdermal estradiol (Climara, Estraderm, FemPatch, Noven, Vivelle, Vivelle-Dot)
Increases synthesis of DNA, RNA, and many proteins in target tissues.
Progestins
Class Summary
Medroxyprogesterone is usually administered to female patients on estrogen replacement therapy for 12-14 d/mo. Induces secretory changes in endometrium and leads to withdrawal bleeding, which is essential for prevention of estrogen-induced endometrial hyperplasia. Patients on combination oral contraceptives already receive a progestin and do not need additional medroxyprogesterone therapy.
Medroxyprogesterone (Provera)
Stops endometrial cell proliferation, allowing organized sloughing of cells after withdrawal. Typically does not stop acute bleeding episode but produces a normal bleeding episode following withdrawal.
Hypothalamic releasing hormones
Class Summary
Pulsatile administration of gonadorelin (GnRH) by subcutaneous (SC) or preferably intravenous (IV) infusion restores pituitary-gonadal axis function and fertility in the majority of people with Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. Some patients with GnRH receptor mutations may respond to high-dose GnRH therapy. Gonadorelin is no longer commercially available in the US.
Gonadorelin (GnRH, Factrel, Lutrepulse)
Stimulates pituitary release of LH.
Gonadotropins
Class Summary
These successfully restore fertility in most patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism. Patients with idiopathic hypogonadotropic hypogonadism and AHC may have an intrinsic defect in spermatogenesis and may not respond to gonadotropin therapy. In men, hCG should be used alone for as long as 1 year and may be effective alone in patients with partial gonadotropin deficiency. Having verified that androgen levels are normal on hCG therapy, FSH should be added to the regimen after that period. In addition, induction of puberty with FSH and LH after a period of FSH priming has been proposed in boys. [39] In females, ovulation induction protocols are complex and vary. A detailed discussion of these protocols is beyond the scope of this review.
Follicle-stimulating hormone (Fertinex, Follistim)
Stimulates gonadal steroid production. Either recombinant or human purified hormone may be used.
Human chorionic gonadotropin (Chorex, Pregnyl, Profasi, Novarel)
Stimulates production of gonadal steroid hormones.
Ovulation stimulators
Class Summary
Clomiphene acts as an antiestrogen to decrease negative estrogen feedback on hypothalamus. In addition, clomiphene may have effects on the pituitary gland and ovaries and can induce ovulation in women with hypothalamic amenorrhea. Clomiphene is not likely to be effective in patients with Kallmann syndrome or idiopathic hypogonadotropic hypogonadism.
Clomiphene citrate (Clomid, Milophene, Serophene)
Stimulates release of pituitary gonadotropins.
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MRI of the brain in patients with Kallmann syndrome (KS) and idiopathic hypogonadotropic hypogonadism (IHH). Panel A is a coronal T1-weighted image of a male with KS showing (abnormal) medially oriented olfactory sulci (black arrows) and normal appearing olfactory bulbs (white arrows). Panel B is an axial T1-weighted image of the same male with KS showing the presence of olfactory sulci (white arrows). Panel C is a coronal T1-weighted image of a female with IHH showing normal olfactory bulbs (large arrows) and sulci (small arrows). Panel D is a coronal T1-weighted image of a female with KS showing lack of olfactory bulbs with shallow olfactory sulci (arrows). (Images reproduced from Quinton R, et al: The neuroradiology of Kallmann's syndrome: a genotypic and phenotypic analysis. J Clin Endocrinol Metab 1996; 81: 3010-3017, with permission from the Endocrine Society).
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This is a frequently sampled serum luteinizing hormone (LH) profile in a male patient with Kallmann syndrome (KS) in comparison with a healthy individual. It shows lack of LH pulsatility in the former.
