Hypogonadism Treatment & Management

Updated: Aug 03, 2022
  • Author: Maria G Vogiatzi, MD; Chief Editor: George T Griffing, MD  more...
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Approach Considerations

Patients with hypogonadism are typically treated with sex steroid replacement. The goals of treatment are:

  • To promote the development of and maintain secondary sexual characteristics and normal sexual function
  • To build and sustain normal bone and muscle mass
  • To assist in the proper psychosocial adjustment of adolescents with hypogonadism

Fertility options can be explored in consultation with a reproductive endocrinologist or urologist. Pulsatile LHRH or gonadotropin therapy can induce fertility in individuals with hypogonadotropic hypogonadism.


Medical Care

In prepubertal patients with hypogonadism, treatment is directed at initiating pubertal development at the appropriate age. Age of therapy initiation takes into account the patient's psychosocial needs, current growth, and growth potential. Treatment entails hormonal replacement therapy with sex steroids, ie, estrogen for females and testosterone for males.

Introduction of sex steroids in such cases starts with the use of small, escalating doses over a period of a couple of years. In females, introduction of puberty can begin with administration of small doses of estrogen given either orally or transdermally. One traditional regimen uses conjugated estrogen starting at doses as low as 0.15 mg daily and titrating upwards in 6-12 month intervals to typically 0.625 mg daily, at which point menses can be induced with the introduction of a progestin. Alternatively, transdermal 17β-estradiol (0.08 to 0.12 mcg estradiol/kg) can be used.

In boys, introduction of puberty is achieved with the use of testosterone, administered intramuscularly or transdermally (in the form of a patch or gel). A typical regimen involves testosterone enanthate injections 50 mg monthly, titrating up to 200-250 mg every 2 weeks, which is a typical adult replacement dose. Adult testosterone dose can be adjusted to maintain serum testosterone concentrations in the normal adult range.

Therapy with sex steroid replacement ensures development of secondary sexual characteristics and maintenance of normal sexual function. In patients with hypergonadotropic hypogonadism, fertility is not possible. However, patients with hypogonadotropic hypogonadism have fertility potential, although therapy with sex steroids does not confer fertility or stimulate testicular growth in men. An alternative for men with hypogonadotropic hypogonadism has been treatment with pulsatile LHRH or hCG, either of which can stimulate testicular growth and spermatogenesis.

Because such treatment is more complex than testosterone replacement, and because treatment with testosterone does not interfere with later therapy to induce fertility, most male patients with hypogonadotropic hypogonadism prefer to initiate and maintain virilization with testosterone. At a time when fertility is desired, it may be induced with either pulsatile LHRH or (more commonly) with a schedule of injections of hCG and FSH. Similarly, fertility can be achieved in females with pulsatile LHRH or exogenous gonadotropin. Such therapy results in ovulation in 95% of women.

A phase III, multicenter, open-label, single-arm trial by Nieschlag et al indicated that corifollitropin-alfa therapy combined with hCG treatment can significantly increase testicular volume and induce spermatogenesis in adult males with hypogonadotropic hypogonadism whose azoospermia could not be cured by hCG treatment alone. Patients in the study who remained azoospermic, though with normalized testosterone levels, after 16 weeks of hCG treatment underwent 52 weeks of twice-weekly hCG therapy along with every-other-week corifollitropin-alfa treatment (150 μg). Mean testicular volume in these patients rose from 8.6 mL to 17.8 mL, while spermatogenesis was induced in more than 75% of subjects. [10]

A literature review by Taniguchi et al indicated that in late-onset hypogonadism, testosterone therapy significantly improves erectile function. This was especially true in patients who were treated with testosterone gel, who underwent more than 30 weeks of treatment, and who had no diabetes mellitus or metabolic syndrome. The mean difference in the International Index of Erectile Function-Erectile Function Domain (IIEF-EFD) score between patients who received testosterone therapy and those who were treated with placebo was 1.86. [11]

The use of oral testosterone preparations, such as 17α-alkylated androgens (eg, methyltestosterone), is discouraged because of liver toxicity. However, oral testosterone undecanoate is available in some countries and is now approved in the United States. Intramuscular testosterone is available as testosterone enanthate or cypionate. Transdermal testosterone can be administered either in the form of a patch or gel. A nasal testosterone replacement therapy has been approved by the US Food and Drug Administration (FDA) for adult males with conditions such as primary hypogonadism (congenital or acquired) and hypogonadotropic hypogonadism (congenital or acquired) resulting from a deficiency or absence of endogenous testosterone. [12] The recommended dosage is 33 mg/day in three divided doses. The drug has not been approved for males younger than 18 years.

For older men with testosterone deficiency, a review by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) found that the evidence concerning the risk of serious cardiovascular side effects from the use of testosterone in men with hypogonadism was inconsistent. [13, 14] The PRAC determined that the benefits of testosterone outweigh its risks but stressed that testosterone-containing medicines should be used only when lack of testosterone has been confirmed by signs and symptoms, as well as by laboratory tests. However, a literature review by Albert and Morley indicated that testosterone supplementation in males aged 65 years or older may increase the risk of cardiovascular events, particularly during the first year of treatment, although intramuscular testosterone seemed to carry less risk than other forms. [15]

On the other hand, a study by Traish et al suggested that long-term testosterone therapy in men with hypogonadism significantly reduces cardiovascular disease–related mortality. Patients in the study’s testosterone-treated group (n=360) underwent therapy for up to 10 years, with median follow-up being 7 years. The investigators found no cardiovascular event–related deaths in the treated patients, compared with 19 such deaths in the group that received no testosterone therapy (n=296). According to the study, mortality in the testosterone-treated patients was reduced by an estimated 66-92%. [16]

A literature review by Corona et al indicated that testosterone replacement therapy is safe for age- or comorbidity-related (functional) male hypogonadism, not just for the organic variety. The investigators reported that the safety of testosterone replacement therapy in functional cases, with regard to cardiovascular and venous thromboembolism risk, as well as prostate concerns, is high enough to allow for the treatment. [17]

The latest Endocrine Society clinical practice guidelines suggest testosterone therapy for men receiving high doses of glucocorticoids who also have low testosterone levels, to promote bone health. The guidelines also suggest such therapy in human immunodeficiency virus (HIV)–infected men with low testosterone levels, to maintain lean bone mass and muscle strength.


Surgical Care

Because of the significant risk of gonadoblastoma and carcinoma, gonadal tissue should be removed in females with karyotypes containing a Y chromosome. This situation is observed in females with XY gonadal dysgenesis or in patients with Turner syndrome who have a karyotype that contains a Y chromosome (usually in 1 of 2 or more mosaic karyotypes). Males with nonfunctioning testicular tissue should undergo orchiectomy and replacement with prostheses.



Consultation with a reproductive endocrinologist or urologist is required for patients with hypogonadotropic hypogonadism who would like to become fertile. Administration of pulsatile LHRH or gonadotropins in females results in ovulation in 95% of the cases. In males, pulsatile LHRH therapy or hCG alone or in combination with gonadotropins can induce spermatogenesis and results in normal adult male testosterone levels.

Patients with hypergonadotropic hypogonadism are traditionally considered infertile. However, men with Klinefelter syndrome may benefit from a consultation with a reproductive urologist and testicular sperm extraction (TESE) followed by in vitro fertilization. This technique has allowed men with Klinefelter syndrome to father children. For boys with Klinefelter syndrome who have reached puberty, cryopreservation of semen samples containing very low numbers of spermatozoa is possible and should be offered before testosterone supplementation, since supplementation may suppress spermatogenesis.



In men, complications of untreated hypogonadism include loss of libido, failure to achieve physical strength, the social implications of failing to go through puberty with peers (if hypogonadism occurs before puberty), and osteoporosis. In addition, if hypogonadism occurs before epiphyseal closure, the result is usually tall stature with a eunuchoid body habitus. Males with hypergonadotropic hypogonadism are typically infertile, although procedures such as TESE have resulted in fertility in Klinefelter syndrome. Men who have hypogonadism due to hypothalamic or pituitary dysfunction can potentially become fertile with administration of gonadotropins.

A retrospective study by Baillargeon et al indicated that males with untreated hypogonadism are at increased risk for the development of any rheumatic autoimmune disease, as well as for rheumatoid arthritis and lupus. [18]

In women with hypogonadism, complications include the social implication of failing to go through puberty with peers (if hypogonadism occurs before puberty). An additional concern for untreated women is osteoporosis, which can be avoided with estrogen replacement. Women who have hypogonadism because of hypothalamic or pituitary dysfunction can potentially become fertile with administration of gonadotropins. Women with primary hypogonadism are infertile; however, with in vitro fertilization using a donor ovum, these women can carry an infant to term.

Osteoporosis has an earlier onset in individuals with hypogonadism; hence, bone mineral density should be compared with age-matched normative standards, and followed longitudinally. Prescribe treatment using appropriate therapeutic interventions.


Long-Term Monitoring

Patients with hypogonadism require lifelong treatment, with the exception of persons with congenital hypogonadotropic hypogonadism (spontaneous recovery having been described in 10-20% of these individuals). Patients with hypogonadism receiving hormone replacement therapy are typically evaluated every 6-12 months. Monitoring may include measurement of testosterone concentrations in males, evaluation of bone mass by dual radiographic absorptiometry, and assessment of cardiovascular risk factors.

Polycythemia can be a complication of testosterone replacement. For older adult men with testosterone deficiency, the Endocrine Society clinical guidelines recommend monitoring hematocrit values to avoid polycythemia. Also in these individuals, prostate examination and prostate-specific antigen (PSA) measurements should be performed before testosterone therapy and periodically after treatment is instituted. [3] Referral to a urologist can be considered based on individual assessment for prostate cancer.