Progestogens in Obstetrics and Gynecology 2015th Ed.

12. Progestogens and the Menopause

Eitan Pe’er 

(1)

Gyneco-Endocrinology Unit, Rambam Health Campus, Technion School of Medicine, Haifa, Israel

Eitan Pe’er

Email: eitanpeer@gmail.com

1 Introduction

Progesterone is an essential hormone during the reproductive years. It does not have any physiological role during menopause. Yet many synthetic progestogens, are in clinical use during the menopause and post menopause, most notably as adjunct to estrogen replacement therapy. Progestogens are necessary in order to prevent endometrial hyperplasia caused by unopposed estrogen [1]. In recent years, large clinical trials have shown that the association of progestins with estrogen in HRT might raise the risk of breast cancer [23], but this risk was not confirmed in ongoing clinical studies which have not shown that trend [4]. Newer evidence from molecular and genomic studies suggests that not all progestins have the same effect. As shown in other chapters in this book, there is no “class-effect” of progestogens. Each progestin has its own biocharcteristics regarding breast cancer as in other clinical conditions.

In recent years clinical and new basic data have clearly shown that progesterone has many other properties and functions beside reproduction and pregnancy. Progesterone has been shown to have neuroprotective effects [5] and is used in various brain injuries [6].

Progesterone has both genomic and non-genomic actions. The genomic action is the classical reaction whereby the hormone progesterone, acting as a ligand, connects to its receptor in the nucleus and initiates new mRNA protein synthesis. This is a relatively slow process. The rapid action of progestogens are due to non-genomic actions in which intracellular signaling pathways are activated resulting in alteration of ions fluxes and intracellular calcium concentration within seconds [7]. The non genomic actions also induce second messengers, such as cyclic nucleotides and extracellular regulated kinases [8]. These actions are specific to each individual progestogen. As progestogens differ in actions, proper selection is necessary for successful therapy in treating menopausal symptoms or reducing the risk of diseases associated with the menopause.

2 Progestogens and Osteoporosis

Progestogens alone have a very limited effect on bone mineral density (BMD). But, pretreatment with estrogen for 4–7 days has been shown to induce progesterone receptors in osteoblasts [9]. This explains the beneficial effect on BMD, in all clinical trials in which progestogens were added to estrogen.

Medroxyprogesterone acetate (MPA) decreases BMD, both in the hips and spine, in the first 2 years of use, followed by a slight increase [10]. The effect of norethisterone acetate (NETA) with a low dose of 17β-estardiol on BMD has been investigated in a randomized placebo control study [11]. There was a significant increase in BMD both in the lumbar spine (5.2 %) and the hip (3.1 %) compared to the placebo group (−0.9%). Serum concentration of osteocalcin decreased by approximately 34 %, bone-specific alkaline phosphatase decreased by about 30 %, and C-terminal propepetide of type I collagen decreased by 20 %. Norethisterone is a synthetic progestin derived from 19-nortestosterone. It binds and activates the progesterone receptor twice as much as progesterone itself, with low androgenic and estrogenic activities attributed to its metabolites [12]. NETA alone has been studied in male castrated mice. In this study NETA alone was found to have a slightly protective effect against bone loss [13]. Controversially, inhibition of the nuclear progesterone receptor has been found to augment bone mass, resulting in higher BMD [14].

3 Progesterone, Hot Flush and Night Sweats

Nightly micronized progesterone (300 mg) has been shown to cause an overall decrease in the number of daily hot flushes and night sweats by 59 % [15]. Extension of this study has shown that micronized progesterone is also effective for severe vasomotor symptoms and that progesterone withdrawal is not followed by a rebound increase in vasomotor symptoms [16]. A similar effect has been shown for medroxyprogesterone acetate (MPA) 10 mg/day. Prior et al. [17], carried out a randomized double-blind trial in women after overiectomy. Patients received either conjugated equine estrogen (CEE), (0.6 mg/day) or MPA for 1 year. MPA was found to be equivalent to CEE in the control of vasomotor symptoms in women treated immediately following the surgery [17]. Oral progestins have been shown to be effective for vasomotor symptoms in several randomized placebo controlled trial [1819].

Estrogen alleviates hot flushes by lowering levels of serotonine and noradrenaline in the brain [19]. Progestogens may act in a different manner. Progesterone acts on the hypothalamus changing the frequency of LH pulses, increasing basal temperature and stimulating respiration. Therefore progesterone and progestins have various effects on the hypothalamus, from which hot flushes are thought to generate [20].

4 Progesterone and Venous Thromboembolism

Progestins, when given alone (e.g. progestin only contraceptive pills), carry little, if any, risk of VTE. Randomized controlled studies and meta-analyses of observational studies suggest that the risk of venous thrombo-embolism (VTE) is higher among users of combined estrogen and progestogen than among users of estrogen alone. Oral estrogens increase the VTE risk while transdermal estrogens appear to be safe with respect to thrombotic risk [21]. However, MPA, by activating glucocorticoid receptors, potentiate the vascular effects of thrombin [22]. The ESTHER study (Estrogen and Thromboembolism Risk) looked into the risk of VTE in French postmenopausal women treated with HRT. This study was the first to establish a differential association of VTE risk related to the progestogen used. The results were irrespective of the route of estrogen administration. The results showed that micronized progesterone and pregnane derivates are safer with regard to VTE risk. The norpregnane derivatives were associated with a significant increase in VTE risk [23].

The norpregnanes are potent progestogens with antiestrogenic activity. Women suffering from hyperestrogenic effects, such as breast tenderness or endometrial hyperplasia are more likely to benefit from this type of progestogens.

5 Progesterone and the Brain

Progesterone is metabolized in the brain by 5α-reductase to 5α-dihydroprogesterone. This in turn is further metabolized by 3α-hydroxysteroid dehydrogenase to the neurosteroid allopregnanolone.

The neurosteroids are modulatory ligands for a variety of neurotransmitters and nuclear steroid hormone receptors. Allopregnanolone crosses the blood-brain barrier. It has been shown in rodents, that allopregnanolone is an efficacious proliferative agent (both in vitro and in-vivo studies) [24]. It also decreases amyloid protein in human neural stem cells [25]. Progesterone metabolites exert considerable sedative effects after binding to the GABAA receptor [26]. Neurosteroids such as pregnanolone affect synaptic functions and myelinization. Their action is mediated through inhibition of the glycogen synthase kinase (GSK-3β) pathway (much like most bipolar mood stabilizers such as lithium) [27]. Neurosteroids are modulatory ligands for a variety of neurotransmitters and nuclear steroid hormone receptors. In a mice model with experimental autoimmune encephalomyelitis it has been shown that both the spinal cord and the brain are sensitive to the protective effects of progesterone. Progesterone has been shown to reduce inflammatory reactions commonly seen in MS, by the direct effect of progesterone on astrocytes and microglia [28].

5.1 Progesterone in Alzheimer’s Disease

Estradiol increases the expression of the progesterone-synthesizing enzymes. Estradiol increases the expression in the hypothalamus, and especially in the astrocytes. Astrocytes are the most active steroidogenic cells in CNS and contribute to neuro-protection [29]. Treatment with different types of progestogens found that these compounds may promote neurogenesis, neural survival, myelinization and increases memory [30]. There is some data that suggests that allopregnanolone may maintain the regenerative ability of the brain and also can modify the progression of Alzheimer’s disease [31]. Progesterone has been shown to improve impaired axonal transport, a key event of the aging brain. Reduced axonal transport has been proposed to play an early and causative role in the development of Alzheimer’s disease. In mouse models, reduced axonal transport may lead to aberrant amyloid-β peptide formation and subsequently to neurodegeneration [32].

5.2 Traumatic Brain Injury (TBI)

In TBI, whether post menopausal or not, the use of progesterone was found to be effective in reducing brain damage. This subject is fully discussed in Chap. 14. In brief, data is available showing that progesterone reduces edema, restores the blood-brain barrier, protects against secondary neuronal death and promotes behavioral recovery after TBI [3334]. A phase II clinical trial, the ProTECT study, has shown more than 50 % reduction in mortality in mortality in severe TBI and a statistically significant improvement in functional outcome in patients with moderate BTI, when treatment was administered no later than 2 h after sustaining BTI [35].

6 Conclusion

Progesterone and progestogens have a significant role in various clinical situations throughout life. As the novel actions of progestogens are elucidated it is clear that these hormones have influence on the outcome of many clinical conditions. It is important to bear in mind that there is no class effect of all these compounds. Each has its own clinical, biochemical and molecular specific effects. In depth knowledge of the physio-pathological effects of each progestogen will enable their better use in many clinical conditions such as hot flushes, brain trauma, sleep disorder and more. The most serious clinical side effects are the raised risk of breast cancer associated with some progestogens (e.g. MPA) but not with others such as micronized progesterone. MPA has also been shown to inhibit some of the beneficial effects of estradiol on the CNS. The fact that numerous coregulators affect the end result of ligand-progesterone receptors (both nuclear and membrane) indicates to the complexities of progesterone/progestogens actions. Receptor affinity alone does not determine potency. Our present understanding is that the affinity, potency and efficacy of progestogens are substantially different between the different types of progestogens and are tissue specific.

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