Marc L'Hermite

Circadian Periodicity of Serum Prolactin Concentration in Man

Immunoreactive human serum prolactin of pituitary origin has been measured by a radioimmunoassay developed for ovine prolactin. Blood samples were collected at four-hour intervals during a 24-hour period from 12 non-pregnant women, three pregnant women, and seven adult men. A circadian periodicity was found in serum prolactin concentration, with peak values during the night, between 1 a.m. and 5 a.m. for the non-pregnant women, and at 5 a.m. for the adult men. Mean serum levels of prolactin were 1·5 times higher in non-pregnant women than in men. In women investigated during the last month of their pregnancy the mean serum prolactin levels were 2·3 times higher than in the non-pregnant women, but there was no circadian periodicity.

Current concepts: I. The 24-hour profile of prolactin in depression.

Abstract The 24-hour profile of plasma PRL was studied in 10 patients with unipolar depression and 8 patients with bipolar depression and compared to 18 control profiles obtained in healthy subjects. Alterations in the basal PRL secretion as well as the characteristics of the 24-hour rhythm were found in all patients but differed strikingly according to the type of depressive illness. The basal PRL level was elevated in unipolars, mainly as a result of increased secretion during wakefulness, and lowered in bipolars because of a lack or reduction of sleep-associated elevation. The nocturnal rise of PRL was maintained in unipolars but absent in 75% of the bipolar subjects. The variability of PRL levels around the 24-hour mean appeared to be reduced in both types of affective illness. These abnormalities in the 24-hour profile of PRL could serve as a biological marker of sub-types of depression.

Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review.

Hormone replacement therapy (HRT) in young postmenopausal women is a safe and effective tool to counteract climacteric symptoms and to prevent long-term degenerative diseases, such as osteoporotic fractures, cardiovascular disease, diabetes mellitus and possibly cognitive impairment. The different types of HRT offer to many extent comparable efficacies on symptoms control; however, the expert selection of specific compounds, doses or routes of administration can provide significant clinical advantages. This paper reviews the role of the non-oral route of administration of sex steroids in the clinical management of postmenopausal women. Non-orally administered estrogens, minimizing the hepatic induction of clotting factors and others proteins associated with the first-pass effect, are associated with potential advantages on the cardiovascular system. In particular, the risk of developing deep vein thrombosis or pulmonary thromboembolism is negligible in comparison to that associated with oral estrogens. In addition, recent indications suggest potential advantages for blood pressure control with non-oral estrogens. To the same extent, a growing literature suggests that the progestins used in association with estrogens may not be equivalent. Recent evidence indeed shows that natural progesterone displays a favorable action on the vessels and on the brain, while this might not be true for some synthetic progestins. Compelling indications also exist that differences might also be present for the risk of developing breast cancer, with recent trials indicating that the association of natural progesterone with estrogens confers less or even no risk of breast cancer as opposed to the use of other synthetic progestins. In conclusion, while all types of hormone replacement therapies are safe and effective and confer significant benefits in the long-term when initiated in young postmenopausal women, in specific clinical settings the choice of the transdermal route of administration of estrogens and the use of natural progesterone might offer significant benefits and added safety.

SIMULTANEOUS STUDY OF CORTISOL, GROWTH HORMONE AND PROLACTIN NYCTOHEMERAL VARIATIONS IN NORMAL AND OBESE SUBJECTS. INFLUENCE OF PROLONGED FASTING IN OBESITY

Hourly integrated concentrations (IC) of growth hormone (GH), prolactin (PRL) and cortisol were determined by a continuous sampling procedure in six obese women, before and at the end of a 12 day fast, and in eight normal controls under basal conditions. Hormonal 24 h IC and nyctohemeral variations were calculated from these data. Nyctohemeral rhythms were investigated by the periodogram method.

HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT

ABSTRACT Hormone replacement therapy (HRT) remains the gold standard for treatment of climacteric symptoms in menopausal women; it is relatively safe in healthy subjects for at least 5 years, provided it had been initiated before the age of 60 years and/or within 10 years from menopause. Estrogen probably adds some cardioprotection, that can, however, be obscured by progestogens, especially medroxyprogesterone acetate (MPA). Oral HRT is associated with an increased risk of venous thromboembolism (VTE), gallbladder disease and possibly stroke. The increased occurrence of all these events can be prevented by the use of the transdermal route of estradiol administration; this route seems also advantageous for women with diabetes, hypertension and other cardiovascular risk factors, and also especially with advancing age. Endometrial protection by any progestogen is insufficient in the mid to long term when cyclical, sequential regimens are used; full protection can be secured only by continuous combined estrogen + progestogen. Natural, ‘body-identical’ progesterone, devoid of any androgenic as well as glucocorticoid activities but being slightly hypotensive due to its antimineralocorticoid activity, appears to be the optimal progestogen in terms of cardiovascular effects, blood pressure, VTE, probably stroke and even breast cancer (contrary to synthetic progestogens and particularly MPA, which appear to be mitogenic on breast cells, in synergism with estrogen). HRT optimization can thus be achieved by combining low doses of estrogen given transdermally with micronized oral progesterone; such optimized HRT will allow us to treat symptomatic women for as long as required. Asymptomatic women at risk of (osteoporotic) fractures can also be treated with this optimized HRT as long as their individual risk/benefit ratio remains favorable (thanks to the absence of increased risks of VTE, stroke and breast cancer).

Risks of estrogens and progestogens

The risks and benefits of specific types of postmenopausal estrogens and progestogens are explored: those affecting serum lipids, clotting elements, hepatic proteins synthesis, blood pressure, glucose tolerance, endometrial, breast and cervical cancer. Ethinyl estradiol taken orally is the only estrogen likely to cause gall bladder disease. It also induces liver protein synthesis when taken orally or vaginally. Natural estrogens do not heighten coagulation factors, and may shift towards fibrinolysis. Both ethinyl estradiol and equine estrogens may increase blood pressure, while natural estrogens may decrease it. Similarly natural estrogens induce prostacyclin synthesis, while ethinyl estradiol activates both prostacyclin and thromboxanes. Progestagens, especially so the norprogestins, disturb carbohydrate metabolism and tend to reverse the beneficial effects of estrogens on serum lipids, a 40-70% reduction in risk of mortality from coronary heart disease. A meta- analysis of 23 studies concluded that menopausal estrogens do not increase the risk of breast cancer by a measurable degree, except in high doses and in those predisposed by family history. There is an increased risk of endometrial carcinoma for those taking unopposed estrogens for more than 3-6 years. This can be attenuated by taking combined estrogen-progestins, which will eventually result in absence of bleeding, or a 12-day progestogen course every 4-6 cycles. Oral micronized progesterone decreases blood pressure. The relative androgenic effects of progestins other than the norprogesterone derivatives are less significant. As an alternative to taking a progestogen, a woman could have regular endometrial sampling or abdominal or vaginal sonograms to detect endometrial cancer.

PROLACTIN RELEASE AFTER INJECTION OF THYROTROPHIN-RELEASING HORMONE IN MAN

Abstract Five normal men were injected intra Summary venously 200 μg. of synthetic thyrotrophin-releasing hormone (T.R.H.). Blood was collected every 5 or 10 minutes and assayed for thyroid-stimulating hormone (T.S.H.), human growth hormone, luteinising hormone, hydrocortisone, and pituitary prolactin. T.S.H. levels reached peak values 20 to 40 minutes after the injection. Hydrocortisone, H.G.H., and L.H. did not exhibit any systematic variation. The T.R.H. injection was followed within 5 minutes by a release of prolactin, with a peak value at 10 minutes. These data indicate a lack of specificity of T.R.H. and suggest that in man it acts as a prolactin-releasing factor. Intravenous T.R.H. administration should become a very useful clinical test for the investigation of the hypothalamo-pituitary relationships, with special respect to prolactin secretion.

Gonadotrophin hormone releasing tests in women receiving hormonal contraception.

Gonadotrophin secretion by the pituitary was tested by i.v. injections of synthetic LH and FSH releasing hormone (LHRH) in five normal women between day 21 and day 25 of the luteal phase of the cycle, in twelve women receiving contraception with i.m. injection of medroxyprogesterone acetate and in eight women taking combined oral contraceptives of different varieties. Treatment with oral contraceptives led to a decrease or even to complete suppression of the response and possibly the reserve capacity of both LH and FSH secretions.

Thyrotrophin, prolactin and growth hormone responses to TRH in barbiturate coma and in depression

The effects of 200 μg thyrotrophin‐releasing hormone (TRH) i.v. on thyrotrophin (TSH), prolactin (PRL), growth hormone (GH) and triiodothyronine (T3) were studied in eight patients with barbiturate coma due to attempted suicide, in the same patients after recovery, in eight depressive patients and in eight normal controls. The patients with barbiturate coma presented normal basal TSH and PRL, elevated basal GH and normal PRL but blunted TSH responses to TRH; their GH concentrations varied widely without consistent relation to TRH administration. The same patients after recovery from coma presented normal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a clear‐cut rise in GH (i.e. more than 10 ng/ml) occurred after TRH administration. The depressive patients presented normal basal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a moderate rise in GH (less than 10 ng/ml) occurred after TRH administration. The increment in T3 concentrations 120 min after TKH was found reduced in the comatose patients only. Basal cortisol was measured in all the subjects and found elevated in the comatose patients only. It is concluded that the abnormal TSH and GH responses to TRH observed in patients with barbiturate coma are more likely related to depressive illness than to an effect of barbiturates at the pituitary level. Barbiturates might affect thyroid secretion.

ACUTE ENDOCRINE PROFILE OF SULPIRIDE IN THE HUMAN

Normal men and normally menstruating women received i.m. injections of 0.1 to 4.0 mg/kg sulphide. This psychotropic drug induced a very rapid (already significant after 5 minutes) and sustained (still significant after 7 hours) elevation of prolactin (PRL) concentrations in all subjects with no consistent modification of LH and FSH. After injection of 4.0 mg/kg, there was similarly no modification of mean TSH concentrations in the women tested in the luteal phase, as well as of mean GH levels in men. Sulpiride prevented the inhibitory effect on PRL levels of 500 mg levodopa, administered orally simultaneously; levodopa administered 2 hours prior to sulpiride failed to counteract the PRL‐stimulatory effect of sulpiride. Under chronic sulpiride‐induced hyperprolactinaemia, levodopa exhibited however a very slight inhibitory effect on PRL concentrations. These data are in agreement with the hypothesis that sulpiride acts mainly at the pituitary level by blocking dopamine receptors of the lactotropes and support the concept that the menstrual cycle perturbations observed under chronic sulpiride administration result from hyperprolactinaemia itself or from a mechanism quite similar to that by which sulpiride induces hyperprolactinaemia.