Sex hormones

Sex hormones

LASA filenames: LASAC863

Contact: Laura Schaap

Background of FSH and LH
The gonads – the ovaries and the testes- secrete steroid hormones that regulate the growth, development and function of a variety of target tissues. Animal experiments implicate the pituitary gland in the control of gonadal function. Two pituitary hormones possessing gonadotropic activity (gonadotropins) were obtained.

Follicle Stimulating Hormone (FSH)
In the male, FSH is responsible for the initial steps of spermatid maturation. It’s role is:
1 – to increase the number of LH receptors of testicular Leydig cells so that they are sensitive to the actions of LH;
2 – to act together with LH to stimulate spermatogenesis.
In fact, FSH and testosterone are required for the initiation of spermatogenesis during sexual maturation.

In the female, FSH is responsible for the early development of the ovarian follicle. FSH functions as the inducer of granulosa cell LH receptor acquisition. This induction of LH receptors is a critical aspect of granulosa cell differentiation and ovarian follicular development.

Luteinizing Hormone (LH)
In the male, LH stimulates testosterone synthesis by the interstitial cells or Leydig cells of the testes. The action of LH is dependent on FSH induction of Leydig cell LH receptors. Indirectly LH stimulates spermatogenesis by way of its effect on testosterone biosynthesis. LH is also responsible for development of secondary sexual characteristics.

In the female, LH stimulates corpora lutea formation and ovulation.

Background of testosterone, estradiol and SHBG
Serum concentrations of estradiol and testosterone decrease with age in both sexes, whereas an increase in sex-hormone binding globulin (SHBG) is seen. Testosterone is an androgen and is largely produced by the testis, but is also synthesized in smaller amounts in the ovaries. Substantial amounts of the testosterone in women are also derived from estradiol. Estradiol is produced in the ovaries in women. Most of the estradiol produced in men is formed by aromatisation of circulating androgens. A smaller part of the estradiol is directly secreted by the testicles. Serum testosterone as well as estradiol are mainly bound to SHBG and albumin. The free fraction (1-3%) and albumin-bound part (35-55%) of testosterone and estradiol are often called bioavailable (non-SHBG-bound) testosterone and estradiol, and are considered as the fractions that are directly available for the target tissues (1).
The results of some studies suggest that low serum levels of hormones, including vitamin D (2), sex hormones (3) and insulin-like growth factor (IGF-1) (4), are associated with immobility and an increased risk of falling. One study (5) on the effect of hormone replacement therapy (HRT) reports a protective effect on the risk of falling among early postmenopausal women. In another study (6), the incidence of falls did not differ between users and non-users of estrogen therapy. It is unclear whether low levels of estradiol in women are related to a decrease in muscle strength. Studies on the effect of estrogen therapy on postural balance and muscle strength in women are contradictory. Some studies found a positive effect of estrogen therapy on muscle strength and/or balance (7-9), while others reported no effect (10-12).
Accumulating evidence suggests that in ageing men, low serum levels of bioavailable testosterone are associated with low muscle strength (13;14) FQUOTE “” . However, the association between testosterone and muscle strength and poor mobility is not clear. Until recently, not much attention has been paid to the role of estradiol in men. One study found that estradiol levels were not associated with muscle strength and body composition in men (18). Adequate estradiol levels are required in men to maintain bone mass.

Changes in LH and FSH concentrations with advancing age
Advancing age in the male generally goes along with a progressive decline in the synthesis of testosterone by Leydig cells, accompanied by an increase of LH and FSH levels. Low testosterone levels with low gonadotropins levels can indicate pituitary dysfunction.
In the female, the onset of menopause results from the loss of cyclic activity of the ovary. Fertility begins to decline about 10 years before the menopause and by age of 50 most primary follicles have been lost. As women approach menopause, there may be a striking increase in serum FSH levels relative to those of LH. Eventually, as estradiol secretion falls to low levels, both FSH and LH concentrations rise and remain elevated.

Measurements in LASA

Blood collection
Participants were invited to the VU University Medical Center (VUMC) or a health care center where blood and urine samples were obtained in the morning after a light (calcium-free) breakfast (n = 1,321). Blood was put on ice immediately, and processed within 60 minutes. Levels of sex hormones and sex-hormone binding globulin (SHBG) were determined in 1,302 persons. Blood samples were obtained during the examination in 1995/96 and stored as serum plasma at -80°C until determination.

Measurement procedure
Testosterone, estradiol and SHBG concentrations were measured by radioimmunoassay (Coat-A-Count, DPC, Los Angeles, USA for testosterone; Diasorin Biomedica, Saluggia, Italy for estradiol; Orion Diagnostica, Espoo, Finland for SHBG); LH and FSH were measured by Immunometric fluorescention assay (Delfia, Wallac Turku Finland). For intra-assay coefficient of variation (CV) see the Table 1.
Levels of testosterone were not measured in women, as very low levels are difficult to measure.

Table 1. VU University Medical Center Endocrinology Laboratory normal values:

Availability of data per wave

Numbers per wave

* 2B=baseline second cohort;
3B=baseline third cohort

Handling of the data
We used various estimates of the levels of bioactive testosterone and estradiol: total testosterone and total estradiol, testosterone/SHBG ratio, estradiol/SHBG ratio, calculated free testosterone and calculated bioavailable (non-SHBG-bound) testosterone. Calculated free and bioavailable testosterone were determined according to the method described by Vermeulen et al. (19), taking the concentration of testosterone, estradiol, SHBG and albumin into account. Calculated free estradiol and bioavailable estradiol levels in women could not be estimated, as levels of testosterone were not measured in women.

The testosterone/SHBG ratio can be calculated as follows: (testosterone/SHBG)*100
The same method accounts for the estradiol/SHBG ratio.

The method of Vermeulen et al. to calculate free and bioavailable testosterone can be found at www.issam.ch/freetesuit.htm (or see appendix). Table 2 shows the method for converting testosterone from nmol/l to ng/dl or vice versa.

The method of Vermeulen seems to approach bioactive levels of testosterone more closely than total testosterone or the testoterone/SHBG ratio (20). However, the testosterone/SHBG ratio is still an often used measure.
Furthermore, it is possible that the method by Vermeulen will be modified/improved over time. Always check the latest literature!

Table 2. Method for converting testosterone from nmol/l to ng/dl or v.v.

Table 3. Sex hormone collection laboratory of Endocrinology, VU University Medical Center
NB. CV % is sample- and concentration dependent (Italic: from instruction leaflet) – old methods are marked.
(September 2004)

Previous use in LASA
Manuscripts in preparation by Schaap, L.A. and Kuchuk, N.O.

• Joshi, D., Van Schoor , N.M., De Ronde, W., Schaap, L.A., Comijs, H.C., Beekman, A.T.F., Lips, P.T.A. (2010). Low free testosterone levels are associated with prevalence and incidence of depressive symptoms in older men. Clinical Endocrinology, 72, 232-240.
• Kuchuk, N.O., Van Schoor , N.M., Pluijm, S.M.F., Smit, J.H., De Ronde, W., Lips, P.T.A. (2007). The association of sex hormone levels with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women. Clinical Endocrinology, 67, 295-303.
• Limonard, E.J., Van Schoor , N.M., De Jongh, R.T., Lips, P.T.A., Fliers, E., Bisschop, P.H. (2015). Osteocalcin and the pituitary-gonadal axis in older men: a population-based study. Clinical Endocrinology, 82, 5, 753-759.
• Pluijm, S.M.F., Visser, M., Smit, J.H., Popp-Snijders, C., Roos, J.C., Lips, P.T.A. (2001). Determinants of bone mineral density in older men and women: body composition as mediator. Journal of Bone and Mineral Research, 16, 2142-2151.
• Rafiq, R., Van Schoor, N.M., Sohl, E., Zillikens, M.C., Oosterwerff, M.M., Schaap, L.A., Lips, P.T.A., De Jongh, R.T. (2016). Associations of vitamin D status and vitamin D-related polymorphisms with sex hormones in older men. The Journal of Steroid Biochemistry and Molecular Biology, 164, 11–17.
• Schaap, L.A., Pluijm, S.M.F., Deeg, D.J.H., Penninx, B.W.J.H., Nicklas, B.J., Lips, P.T.A., Harris, T.B., Newman, A.B., Kritchevsky, S.B., Cauley, J.A., Goodpaster, B.H., Tylavsky, F.A., Yaffe, K., Visser, M. (2008). Low testosterone levels and decline in physical performance and muscle strength in older men: findings from two prospective cohort studies. Clinical Endocrinology, 68, 42-50.
• Schaap, L.A., Pluijm, S.M.F., Smit, J.H., Van Schoor , N.M., Visser, M., Gooren, L.J.G., Lips, P.T.A. (2005). The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women. Clinical Endocrinology, 63, 152-160.

Appendix A: Calculation of free and bioavailable testosterone (pdf)

Appendix B: syntax for steroid hormones (pdf

References

1. van den Beld AW, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men. J Clin Endocrinol Metab 2000; 85(9):3276-3282.
2. Stein MS, Wark JD, Scherer SC et al. Falls relate to vitamin D and parathyroid hormone in an Australian nursing home and hostel. J Am Geriatr Soc 1999; 47(10):1195-1201.
3. Randell KM, Honkanen RJ, Komulainen MH, Tuppurainen MT, Kroger H, Saarikoski S. Hormone replacement therapy and risk of falling in early postmenopausal women – a population-based study. Clin Endocrinol (Oxf) 2001; 54(6):769-774.
4. Cappola AR, Bandeen-Roche K, Wand GS, Volpato S, Fried LP. Association of IGF-I levels with muscle strength and mobility in older women. J Clin Endocrinol Metab 2001; 86(9):4139-4146.
5. Seeley DG, Cauley JA, Grady D, Browner WS, Nevitt MC, Cummings SR. Is postmenopausal estrogen therapy associated with neuromuscular function or falling in elderly women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 1995; 155(3):293-299.
6. Hammar ML, Lindgren R, Berg GE, Moller CG, Niklasson MK. Effects of hormonal replacement therapy on the postural balance among postmenopausal women. Obstet Gynecol 1996; 88(6):955-960.
7. Skelton DA, Phillips SK, Bruce SA, Naylor CH, Woledge RC. Hormone replacement therapy increases isometric muscle strength of adductor pollicis in post-menopausal women. Clin Sci (Lond) 1999; 96(4):357-364.
8. Naessen T, Lindmark B, Larsen HC. Better postural balance in elderly women receiving estrogens. Am J Obstet Gynecol 1997; 177(2):412-416.
9. Goebel JA, Birge SJ, Price SC, Hanson JM, Fishel DG. Estrogen replacement therapy and postural stability in the elderly. Am J Otol 1995; 16(4):470-474.
10. Bemben DA, Langdon DB. Relationship between estrogen use and musculoskeletal function in postmenopausal women. Maturitas 2002; 42(2):119-127.
11. Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ. Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 1999; 107(2):123-136.
12. Ferrando AA, Sheffield-Moore M, Yeckel CW et al. Testosterone administration to older men improves muscle function: molecular and physiological mechanisms. Am J Physiol Endocrinol Metab 2002; 282(3):E601-E607.
13. Brill KT, Weltman AL, Gentili A et al. Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J Clin Endocrinol Metab 2002; 87(12):5649-5657.
14. Schroeder ET, Singh A, Bhasin S et al. Effects of an oral androgen on muscle and metabolism in older, community-dwelling men. Am J Physiol Endocrinol Metab 2003; 284(1):E120-E128.
15. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. Clin Endocrinol Metab 1999; 84(10):3666-72.
16. Hadley, Mac E. Endocrinology. –3rd edition, 1992.
17. Laboratoriumbepalingen: referenties, procedures, informatie. VU academisch ziekenhuis, juni 2000.
18. Schill, W-B. Fertility and sexual life of men after their forties and in older age. Asian J Androl. 2001 Mar;3(1):1-7. Review.

Date of last update: April 6, 2020