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Willem de Ronde, Albert Hofman, Huibert A P Pols and Frank H de Jong

Objective: The origin of oestrogens in men is only partly understood. From infusion studies with radioactively labelled hormones, we know that oestradiol (E2) and oestrone (E1) are either directly secreted by the testes and adrenal glands or peripherally produced from testicular or adrenal androgens.

Design and methods: We determined E2, E1, androstenedione, testosterone and dehydroepiandroster-one sulphate (DHEAS) in 292 elderly men and 367 postmenopausal women. We considered post-menopausal women as men without testes, assuming that the postmenopausal ovary is not endocrinologically active and that the testes do not contribute to circulating levels of DHEAS. Subjects were stratified by DHEAS levels to adjust for differences in DHEAS levels between sexes. For men and women separately, mean levels of E2, E1, androstenedione and testosterone were calculated per DHEAS stratum. The relative direct and indirect contributions of the testes to steroid levels in men were calculated by the formula [(Cm −Cf)/Cm] × 100%, in fwhich Cm and Cf represent the mean concentrations of the steroid in men and women respectively.

Results: The relative contributions (%) of the testes to hormone levels per DHEAS stratum (<2, 2–4, 4–6 and >6 μmol/l) respectively were, for E2, 72%, 60%, 52% and 44%; for E1, 54%, 47%, 35% and 34%; for androstenedione, 14%, 4%, 12% and 0%; and, for testosterone, 88%, 88%, 87% and 83%.

Conclusions: We conclude that in elderly men dependent on DHEAS levels, 44–72% of E2 and 34–54% of E1 originate directly or indirectly from the testes.

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Grietje Dijkstra, Dirk G de Rooij, Frank H de Jong and Robert van den Hurk

Dijkstra G, de Rooij DG, de Jong FH, van den Hurk R. Effect of hypothyroidism on ovarian follicular development, granulosa cell proliferation and peripheral hormone levels in the prepubertal rat. Eur J Endocrinol 1996;134:649–54. ISSN 0804–4643

The aim of this study was to examine the effects of prepubertal hypothyroidism on ovarian development in rats. Therefore, from birth up to day 40 postpartum, rats were given 6-propyl-2-thiouracil (PTU) via the drinking water of mothers and pups. At ages ranging from 12 to 40 days, ovarian weights were measured and serum was collected to estimate thyrotrophin (TSH), folliclestimulating hormone (FSH) and inhibin levels. Two hours before sacrifice the animals received an injection of bromodeoxyuridine (BrdU) to estimate the proliferative activity of the follicular granulosa cells. Ovaries were fixed in Carnoy's fluid and follicle counts were performed on sections stained with anti-BrdU and with haematoxylin and eosin. The PTU treatment resulted in increased serum TSH levels, indicative of hypothyroidism, and markedly lower body and ovarian weights, whereas serum FSH and inhibin levels were hardly affected. At day 40, ovaries of PTU-treated animals contained relatively more secondary and less antral follicles, smaller non-atretic antral follicles and more atretic follicles when compared with untreated rats, while corpora lutea were absent. It is concluded that this disturbed folliculogenesis is due to inadequate thyroid hormone supply, which hampers the differentiation and not the proliferation of granulosa cells because diameters of antral follicles were significantly smaller whereas the BrdU-labelling index had not changed.

Robert van den Hurk, Department of Functional Morphology, Faculty of Veterinary Medicine, PO Box 80.157, 3508 TD Utrecht, The Netherlands

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Steven W.J. Lamberts, Jan G. M. Klijn, Frank H. de Jong and Jan C. Birkenhäger

Abstract.

The recovery of the hypothalamo-pituitary-adrenal axis after selective transsphenoidal adenomectomy was studied in 3 patients with Cushing's disease by measuring basal plasma ACTH and cortisol concentrations, cortisol secretion rate, the diurnal rhythm of cortisol, and the reaction of cortisol to lysine vasopressin (LVP), of compound S to metyrapone and of cortisol and growth hormone to an insulin-induced hypoglycaemia. The third patient had been treated previously by external pituitary irradiation. In 2 patients basal plasma ACTH levels returned within normal values before plasma cortisol, but no supra-physiological plasma concentrations of ACTH were seen as has been observed after withdrawal of exogenous glucocorticoids. With regard to the different stimulation tests: at first the normal reaction of plasma cortisol to LVP returned after 3 months, at the same time as the restoration of growth hormone secretion in response to hypoglycaemia. A normalization of the reaction to metyrapone was seen thereafter while finally the reaction of cortisol to an insulin-induced hypoglycaemia and the diurnal rhythm of plasma cortisol returned 15 to 18 months after operation in the first patient and after 12 months in the second patient. Selective adenomectomy had also been carried out in the third patient, as evidenced by normal TSH, LH and FSH secretion. Hypocortisolism, and a deficient ACTH and growth hormone secretion in response to the stimuli mentioned, however, did not normalize up till 22 months after operation. The restoration of the hypothalamo-pituitary-adrenal axis after selective pituitary adenomectomy in Cushing's disease was prevented in this patient by prior external pituitary irradiation.

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Dick C Schoot, Wim C Hop, Thierry D Pache, Frank H de Jong and Bart CJM Fauser

The aim of this study was to investigate the late follicular phase of seven gonadotrophin-treated patients with polycystic ovary syndrome (PCOS) exhibiting monofollicular growth and to compare developmental characteristics with the dominant follicle in seven regularly cycling control women. Daily serum follicle-stimulating hormone (FSH) levels in patients with PCOS decreased more rapidly compared to controls (−0.3±0.2 IU/day in controls versus −0.7±0.4 IU/day in PCOS; p<0.02). No statistically significant differences were seen in daily increase (30% in controls and PCOS) and mean peak levels (825±94 pmol/l in controls versus 937±231 pmol/l in PCOS) of oestradiol (E2) serum levels when comparing both groups. Mean daily growth of the dominant follicle (1.7±0.4 mm in controls versus 1.9±0.6 mm in PCOS) was not significantly different. It is concluded from the present study that in patients with PCOS treated with gonadotrophin plus adjuvant gonadotrophin-releasing hormone agonist, development of a single follicle can occur using a decreasing dose regimen resulting in decreasing serum FSH levels. In addition, growth and oestrogen production by the dominant follicle in PCOS is not significantly different from follicle growth under normal conditions.

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Alexander V Sluijmer, Maas J Heineman, Johannes LH Evers and Frank H de Jong

In a patient with a granulosa cell tumour, stage 1a1, peripheral and ovarian vein blood samples were drawn before, during and after bilateral oophorectomy. Before operation inhibin and follicle-stimulating hormone levels were in the premenopausal range, whereas the peripheral level of oestradiol and luteinizing hormone were in the normal postmenopausal range. In the ovarian vein at the side of the tumour, inhibin and oestradiol levels were elevated, whereas in the contralateral ovarian vein the concentrations of inhibin and oestradiol were in the same range as in the peripheral vein. Immunoreactive inhibin levels in the homogenized tumour were 23 times higher than in the contralateral ovary, whereas inhibin bioactivities in the same samples amounted to 126 and 14 U/mg protein, respectively. After removal of the tumour, peripheral serum follicle-stimulating hormone and inhibin levels were in the normal postmenopausal range again. We conclude that inhibin can have a role as a marker for granulosa cell tumours.

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Femke P Hohmann, Joop S E Laven, Frank H de Jong and Bart C J M Fauser

Objective: To investigate the relationship between serum concentrations of inhibin A, inhibin B and estradiol (E2) and the number of developing follicles during the administration of exogenous follicle-stimulating hormone (FSH) in various regimens in normo-ovulatory volunteers and to evaluate if inhibins act as suitable markers for the number of developing follicles during ovarian stimulation.

Design and methods: Serial hormone determinations and assessment of follicle numbers were carried out during unstimulated cycles and during various interventions with exogenous FSH. Subjects were randomized for FSH administration into the following groups: a single high dose (375 IU) during the early follicular phase (group A), 5 consecutive low doses (75 IU/day) starting in the mid follicular phase (group B) or daily low doses (75 IU/day) during the early to late follicular phase (starting on cycle days 3, 5 or 7; groups C, D and E respectively).

Results: Extending the FSH window increases the number of small antral follicles and hence inhibin B serum concentrations. If such an intervention results in multi-follicular growth, mid follicular phase inhibin B (P = 0.001) as well as late follicular phase inhibin B and inhibin A levels are significantly (P < 0.05 and P < 0.01 respectively) increased compared with mono-follicular cycles or the natural cycle. Although mid follicular inhibin B levels correlated well with the number of small antral (P < 0.05) and pre-ovulatory (P < 0.001) follicles in the late follicular phase, mid follicular inhibin A and estradiol serum concentrations only correlated with the number of pre-ovulatory follicles (P < 0.001 and P < 0.01 respectively).

Conclusions: The present data extend our understanding of the relationship between follicle dynamics, serum inhibins and FSH during ovarian hyperstimulation. However, although mid follicular inhibin B does correlate with the number of developing follicles, it does not facilitate the identification of women at risk for multiple follicle development.

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Catherine E de Keyser, Filipe Valerio de Lima, Frank H de Jong, Albert Hofman, Yolanda B de Rijke, André G Uitterlinden, Loes E Visser and Bruno H Stricker

Objective

Statins, or HMG-CoA reductase inhibitors, decrease cholesterol production. Because cholesterol is a precursor of the testosterone biosynthesis pathway, there is some concern that statins might lower serum testosterone levels. The objective of the present study was to investigate the association between the use of statins and serum testosterone levels in men.

Design

Cross-sectional study within the prospective population-based Rotterdam Study.

Subjects and methods

We included 4166 men with available data on total testosterone, non-sex hormone-binding globulin (SHBG)-bound testosterone, and medication use. Multivariable linear regression analysis was used to compare the differences in serum testosterone levels (nmol/l) between current, past, and never statin users. We considered dose and duration of use. Analyses were adjusted for age, BMI, cardiovascular disease, diabetes mellitus, hypertension, and estradiol levels.

Results

We identified 577 current (mean age 64.1 years), 148 past (mean age 64.6 years), and 3441 never (mean age 64.6 years) statin users. Adjusted for all covariables, current statin use of 1–≤6 months or >6 months was significantly associated with lower total testosterone levels as compared to non-users (β −1.24, 95% CI −2.17, −0.31, and β −1.14, 95% CI −2.07, −0.20 respectively). Current use of 1–≤6 months was also associated with significantly lower non-SHBG-bound testosterone levels (β −0.42, 95% CI −0.82, −0.02). There was a trend toward lower testosterone levels at higher statin doses both for total (P trend 2.9×10−5) and non-SHBG-bound (P trend 2.0×10−4) testosterone. No association between past statin use and testosterone levels was found.

Conclusion

We showed that current use of statins was associated with significantly lower serum total and non-SHBG-bound testosterone levels. The clinical relevance of this association should be further investigated.

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Johannes Hofland, Richard A Feelders, Ronald van der Wal, Michiel N Kerstens, Harm R Haak, Wouter W de Herder and Frank H de Jong

Objective

The insufficient diagnostic accuracy for differentiation between benign and malignant adrenocortical disease and lack of sensitive markers reflecting tumor load emphasize the need for novel biomarkers for diagnosis and follow-up of adrenocortical carcinoma (ACC).

Design

Since the inhibin α-subunit is expressed within the adrenal cortex, the role of serum inhibin pro-αC as a tumor marker for ACC was studied in patients.

Methods

Regulation of adrenal pro-αC secretion was investigated by adrenocortical function tests. Serum inhibin pro-αC levels were measured in controls (n=181) and patients with adrenocortical hyperplasia (n=45), adrenocortical adenoma (ADA, n=32), ACC (n=32), or non-cortical tumors (n=12). Steroid hormone, ACTH, and inhibin A and B levels were also estimated in patient subsets.

Results

Serum inhibin pro-αC levels increased by 16% after stimulation with ACTH (P=0.043). ACC patients had higher serum inhibin pro-αC levels than controls (medians 733 vs 307 ng/l, P<0.0001) and patients with adrenocortical hyperplasia, ADA, or non-adrenocortical adrenal tumors (148, 208, and 131 ng/l, respectively, P=0.0003). Inhibin pro-αC measurement in ACC patients had a sensitivity of 59% and specificity of 84% for differentiation from ADA patients. Receiver operating characteristic analysis displayed areas under the curve of 0.87 for ACC vs controls and 0.81 for ACC vs ADA (P<0.0001). Surgery or mitotane therapy was followed by a decrease of inhibin pro-αC levels in 10/10 ACC patients tested during follow-up (P=0.0065).

Conclusions

Inhibin pro-αC is produced by the adrenal gland. Differentiation between ADA and ACC by serum inhibin pro-αC is limited, but its levels may constitute a novel tumor marker for ACC.

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Nicole G M Beckers, Peter Platteau, Marinus J Eijkemans, Nicholas S Macklon, Frank H de Jong, Paul Devroey and Bart C J M Fauser

Objective: The luteal phase after ovarian hyperstimulation for in vitro fertilization (IVF) is insufficient. Therefore, luteal phase supplementation is routinely applied in IVF. It may be postulated that premature luteolysis after ovarian hyperstimulation is due to supraphysiological steroid levels in the early luteal phase. In the present study, high doses of steroids are administered after the LH surge in normo-ovulatory volunteers in order to investigate whether this intervention gives rise to endocrine changes and a shortening of the luteal phase.

Design: Randomized controlled trial.

Methods: Forty non-smoking, normal weight women, between 18 and 37 years of age, with a regular menstrual cycle (24–35 days), received either high dosages of estradiol (E2), progesterone (P), E2+P or no medication. Blood sampling was performed every other day from the day of the LH surge until LH+14. Duration of the luteal phase and endocrine profiles were the main study outcomes.

Results: Early luteal phase steroid concentrations achieved by exogenous administration were comparable with levels observed following ovarian hyperstimulation for IVF. No difference in the luteal phase length was observed comparing all groups. However, a significant decrease in LH levels could be observed 6 days after the mid-cycle LH surge (P<0.001) in women receiving P, resulting in accelerated decrease of inhibin A production by the corpus luteum (P=0.001).

Conclusion: The present intervention of high-dose steroid administration shortly after the LH surge failed to induce a premature luteolysis regularly in cyclic women. It seems that the induced transient suppression in LH allowed for a timely recovery of corpus luteum function. Other additional factors may be held responsible for the distinct reduction in luteal phase length observed after ovarian hyperstimulation for IVF.

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Johannes Hofland, Wouter W de Herder, Lieke Derks, Leo J Hofland, Peter M van Koetsveld, Ronald R de Krijger, Francien H van Nederveen, Anelia Horvath, Constantine A Stratakis, Frank H de Jong and Richard A Feelders

Context

Primary pigmented nodular adrenocortical disease (PPNAD) can lead to steroid hormone overproduction. Mutations in the cAMP protein kinase A regulatory subunit type 1A (PRKAR1A) are causative of PPNAD. Steroidogenesis in PPNAD can be modified through a local glucocorticoid feed-forward loop.

Objective

Investigation of regulation of steroidogenesis in a case of PPNAD with virilization.

Materials and methods

A 33-year-old woman presented with primary infertility due to hyperandrogenism. Elevated levels of testosterone and subclinical ACTH-independent Cushing's syndrome led to the discovery of an adrenal tumor, which was diagnosed as PPNAD. In vivo evaluation of aberrantly expressed hormone receptors showed no steroid response to known stimuli. Genetic analysis revealed a PRKAR1A protein-truncating Q28X mutation. After adrenalectomy, steroid levels normalized. Tumor cells were cultured and steroidogenic responses to ACTH and dexamethasone were measured and compared with those in normal adrenal and adrenocortical carcinoma cells. Expression levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) types 3 and 5 and steroid receptors were quantified in PPNAD, normal adrenal, and adrenal adenoma tissues.

Results

Isolated PPNAD cells, analogous to normal adrenal cells, showed both increased steroidogenic enzyme expression and steroid secretion in response to ACTH. Dexamethasone did not affect steroid production in the investigated types of adrenal cells. 17β-HSD type 5 was expressed at a higher level in the PPNAD-associated adenoma compared with control adrenal tissue.

Conclusion

PPNAD-associated adenomas can cause virilization and infertility by adrenal androgen overproduction. This may be due to steroidogenic control mechanisms that differ from those described for PPNAD without large adenomas.